U.S. patent application number 16/638708 was filed with the patent office on 2020-07-09 for novel sulfonamide carboxamide compounds.
This patent application is currently assigned to Inflazome Limited. The applicant listed for this patent is Inflazome Limited. Invention is credited to Angus MACLEOD, David MILLER, Jonathan SHANNON, Stephen ST-GALLAY, Stephen THOM, Jimmy VAN WILTENBURG.
Application Number | 20200216389 16/638708 |
Document ID | / |
Family ID | 63371672 |
Filed Date | 2020-07-09 |
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United States Patent
Application |
20200216389 |
Kind Code |
A1 |
MILLER; David ; et
al. |
July 9, 2020 |
NOVEL SULFONAMIDE CARBOXAMIDE COMPOUNDS
Abstract
The present invention relates to compounds of formula (I):
wherein Q is selected from O or S; R.sup.1 is a saturated or
unsaturated, optionally substituted C.sub.1-C.sub.15 hydrocarbyl
group, wherein the atom of R.sup.1 which is attached to the sulfur
atom of the sulfonylurea group is not a ring atom of a cyclic
group; and R.sup.2 is a cyclic group substituted at the
.alpha.-position, wherein R may optionally be further substituted.
The present invention further relates to salts, solvates and
prodrugs of such compounds, to pharmaceutical compositions
comprising such compounds, and to the use of such compounds in the
treatment and prevention of medical disorders and diseases, most
especially by the inhibition of NLRP.sub.3. ##STR00001##
Inventors: |
MILLER; David; (Cambridge,
GB) ; MACLEOD; Angus; (Cambridge, GB) ; VAN
WILTENBURG; Jimmy; (Groningen, GB) ; THOM;
Stephen; (Nottingham, GB) ; ST-GALLAY; Stephen;
(Nottingham, GB) ; SHANNON; Jonathan; (Nottingham,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Inflazome Limited |
Dublin 2 |
|
IE |
|
|
Assignee: |
Inflazome Limited
Dublin 2
IE
|
Family ID: |
63371672 |
Appl. No.: |
16/638708 |
Filed: |
August 15, 2018 |
PCT Filed: |
August 15, 2018 |
PCT NO: |
PCT/EP2018/072134 |
371 Date: |
February 12, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 213/46 20130101;
C07D 213/52 20130101; C07D 213/40 20130101; C07D 213/84 20130101;
C07C 311/55 20130101; C07D 213/64 20130101; C07C 2603/10
20170501 |
International
Class: |
C07C 311/55 20060101
C07C311/55; C07D 213/84 20060101 C07D213/84; C07D 213/64 20060101
C07D213/64; C07D 213/40 20060101 C07D213/40 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 15, 2017 |
GB |
1713082.4 |
Aug 15, 2017 |
GB |
1713083.2 |
Aug 15, 2017 |
GB |
1713085.7 |
Nov 9, 2017 |
GB |
1718563.8 |
Nov 9, 2017 |
GB |
1718564.6 |
Nov 9, 2017 |
GB |
1718565.3 |
Dec 22, 2017 |
GB |
1721726.6 |
Jul 4, 2018 |
GB |
1810983.5 |
Jul 26, 2018 |
GB |
1812225.9 |
Jul 26, 2018 |
GB |
1812226.7 |
Claims
1. A compound of formula (I): ##STR00101## or a pharmaceutically
acceptable salt, solvate or prodrug thereof, wherein: Q is selected
from O or S; R.sup.1 is a saturated or unsaturated C.sub.1-C.sub.15
hydrocarbyl group, wherein the hydrocarbyl group may be
straight-chained or branched, or be or include cyclic groups,
wherein the hydrocarbyl group may optionally be substituted, and
wherein the atom of R.sup.1 which is attached to the sulfur atom of
the sulfonylurea group is not a ring atom of a cyclic group; and
R.sup.2 is a cyclic group substituted at the .alpha.-position,
wherein R.sup.2 may optionally be further substituted.
2. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 1, wherein R.sup.1 is
substituted with one or more substituents independently selected
from halo, C.sub.1-C.sub.4 haloalkyl, --CN, --N.sub.3, --NO.sub.2,
--OH, --SR.sup..delta., --SOR.sup..delta., --SO.sub.2R.sup..delta.,
--SO.sub.2N(R.sup..delta.).sub.2, --NH.sub.2, --COR.sup..delta.,
--COOR.sup..delta. or --OCOR.sup..delta.; wherein each
--R.sup..delta. is independently selected from hydrogen or a
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4
alkynyl, C.sub.1-C.sub.4 haloalkyl or C.sub.3-C.sub.7 cycloalkyl
group.
3. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 2, wherein R.sup.1 is
substituted with one or more substituents independently selected
from halo, C.sub.1-C.sub.4 haloalkyl, --CN, --N.sub.3,
--SR.sup..delta., --SOR.sup..delta., --SO.sub.2R.sup..delta. or
--SO.sub.2N(R.sup..delta.).sub.2; wherein each --R.sup.0 is
independently selected from hydrogen or a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
haloalkyl or C.sub.3-C.sub.7 cycloalkyl group.
4. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 1, wherein R.sup.2 is a cyclic
group substituted at the .alpha. and .alpha.' positions, wherein
R.sup.2 may optionally be further substituted.
5. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 1, wherein: R.sup.1 is a
saturated or unsaturated C.sub.1-C.sub.7 hydrocarbyl group, wherein
the hydrocarbyl group may be straight-chained or branched, or be or
include cyclic groups, wherein the hydrocarbyl group may optionally
be substituted, and wherein the atom of R.sup.1 which is attached
to the sulfur atom of the sulfonylurea group is not a ring atom of
a cyclic group; and R.sup.2 is a cyclic group substituted at the
.alpha. and .alpha.' positions, wherein R.sup.2 may optionally be
further substituted.
6. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 1, wherein R.sup.2 is a fused
cyclic group, wherein a cycloalkyl, cycloalkenyl, non-aromatic
heterocyclic, aryl or heteroaryl ring is fused to the cyclic group
across the .alpha.,.beta. positions, wherein R.sup.2 is further
substituted at the .alpha.' position, and wherein R.sup.2 may
optionally be further substituted.
7. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 1, wherein R.sup.2 is a fused
cyclic group, wherein a first cycloalkyl, cycloalkenyl,
non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the
cyclic group across the .alpha.,.beta. positions and a second
cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or
heteroaryl ring is fused to the cyclic group across the
.alpha.',.beta.' positions, and wherein R.sup.2 may optionally be
further substituted.
8. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 1, wherein R.sup.2 is an aryl
or a heteroaryl group, wherein the aryl or the heteroaryl group is
substituted at the .alpha.-position, and wherein R.sup.2 may
optionally be further substituted.
9. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 8, wherein R.sup.2 is an aryl
or a heteroaryl group, wherein the aryl or the heteroaryl group is
substituted at the .alpha. and .alpha.' positions, and wherein
R.sup.2 may optionally be further substituted.
10. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 9, wherein R.sup.2 is a fused
aryl or a fused heteroaryl group, wherein a first cycloalkyl,
cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is
fused to the aryl or heteroaryl group across the .alpha.,.beta.
positions and a second cycloalkyl, cycloalkenyl, non-aromatic
heterocyclic, aryl or heteroaryl ring is fused to the aryl or
heteroaryl group across the .alpha.',.beta.' positions, and wherein
R.sup.2 may optionally be further substituted.
11. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 1, wherein R.sup.2 is a cyclic
group substituted at the .alpha.-position with a monovalent
heterocyclic group or a monovalent aromatic group, wherein a ring
atom of the heterocyclic or aromatic group is directly attached to
the .alpha.-ring atom of the cyclic group, wherein the heterocyclic
or aromatic group may optionally be substituted, and wherein the
cyclic group may optionally be further substituted.
12. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 1, wherein Q is O.
13. The compound or a pharmaceutically acceptable salt, solvate or
prodrug thereof as claimed in claim 1, wherein the compound is
selected from the group consisting of: ##STR00102## ##STR00103##
##STR00104##
14. (canceled)
15. A pharmaceutical composition comprising the compound, or a
pharmaceutically acceptable salt, solvate or prodrug thereof as
claimed in claim 14, and a pharmaceutically acceptable
excipient.
16. The pharmaceutical composition as claimed in claim 15, wherein
the pharmaceutical composition is a topical pharmaceutical
composition.
17. (canceled)
18. A method of treating or preventing a disease, disorder or
condition in a subject, the method comprising the step of
administering an effective amount of the compound or a
pharmaceutically acceptable salt, solvate, or prodrug thereof as
claimed in claim 1 to the subject, thereby treating or preventing
the disease, disorder or condition, optionally wherein the disease,
disorder or condition is responsive to NLRP3 inhibition.
19. The method as claimed in claim 18, wherein the disease,
disorder or condition is selected from: (i) inflammation; (ii) an
auto-immune disease; (iii) cancer; (iv) an infection; (v) a central
nervous system disease; (vi) a metabolic disease; (vii) a
cardiovascular disease; (viii) a respiratory disease; (ix) a liver
disease; (x) a renal disease; (xi) an ocular disease; (xii) a skin
disease; (xiii) a lymphatic condition; (xiv) a psychological
disorder; (xv) graft versus host disease; (xvi) allodynia; and
(xvii) any disease where an individual has been determined to carry
a germline or somatic non-silent mutation in NLRP3.
20. The method as claimed in claim 18, wherein the disease,
disorder or condition is selected from: (i) cryopyrin-associated
periodic syndromes (CAPS); (ii) Muckle-Wells syndrome (MWS); (iii)
familial cold autoinflammatory syndrome (FCAS); (iv) neonatal onset
multisystem inflammatory disease (NOMID); (v) familial
Mediterranean fever (FMF); (vi) pyogenic arthritis, pyoderma
gangrenosum and acne syndrome (PAPA); (vii) hyperimmunoglobulinemia
D and periodic fever syndrome (HIDS); (viii) Tumour Necrosis Factor
(TNF) Receptor-Associated Periodic Syndrome (TRAPS); (ix) systemic
juvenile idiopathic arthritis; (x) adult-onset Still's disease
(AOSD); (xi) relapsing polychondritis; (xii) Schnitzler's syndrome;
(xiii) Sweet's syndrome; (xiv) Behcet's disease; (xv)
anti-synthetase syndrome; (xvi) deficiency of interleukin 1
receptor antagonist (DIRA); and (xvii) haploinsufficiency of A20
(HA20).
21. (canceled)
22. The method as claimed in claim 18, wherein the compound is
administered as a pharmaceutical composition further comprising a
pharmaceutically acceptable excipient.
23. A method of inhibiting NLRP3 in a subject, comprising
administering the compound or a pharmaceutically acceptable salt,
solvate or prodrug thereof as claimed in claim 1 to the subject
thereby inhibiting NLRP3.
24. A method of analysing inhibition of NLRP3 or an effect of
inhibition of NLRP3 by a compound, comprising contacting a cell or
non-human animal with the compound or a pharmaceutically acceptable
salt, solvate or prodrug thereof as claimed in claim 1, and
analysing inhibition of NLRP3 or an effect of inhibition of NLRP3
in the cell or non-human animal by the compound.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to sulfonylureas and
sulfonylthioureas comprising a C.sub.1-C.sub.15 hydrocarbyl group
attached to the sulfur atom of the sulfonylurea group and an
.alpha.-substituted cyclic group attached to the nitrogen atom of
the urea group, and to associated salts, solvates, prodrugs and
pharmaceutical compositions. The present invention further relates
to the use of such compounds in the treatment and prevention of
medical disorders and diseases, most especially by NLRP3
inhibition.
BACKGROUND
[0002] The NOD-like receptor (NLR) family, pyrin domain-containing
protein 3 (NLRP3) inflammasome is a component of the inflammatory
process, and its aberrant activity is pathogenic in inherited
disorders such as cryopyrin-associated periodic syndromes (CAPS)
and complex diseases such as multiple sclerosis, type 2 diabetes,
Alzheimer's disease and atherosclerosis.
[0003] NLRP3 is an intracellular signalling molecule that senses
many pathogen-derived, environmental and host-derived factors. Upon
activation, NLRP3 binds to apoptosis-associated speck-like protein
containing a caspase activation and recruitment domain (ASC). ASC
then polymerises to form a large aggregate known as an ASC speck.
Polymerised ASC in turn interacts with the cysteine protease
caspase-1 to form a complex termed the inflammasome. This results
in the activation of caspase-1, which cleaves the precursor forms
of the proinflammatory cytokines IL-1.beta. and IL-18 (termed
pro-IL-1.beta. and pro-IL-18 respectively) to thereby activate
these cytokines. Caspase-1 also mediates a type of inflammatory
cell death known as pyroptosis. The ASC speck can also recruit and
activate caspase-8, which can process pro-IL-1.beta. and pro-IL-18
and trigger apoptotic cell death.
[0004] Caspase-1 cleaves pro-IL-1 and pro-IL-18 to their active
forms, which are secreted from the cell. Active caspase-1 also
cleaves gasdermin-D to trigger pyroptosis. Through its control of
the pyroptotic cell death pathway, caspase-1 also mediates the
release of alarmin molecules such as IL-33 and high mobility group
box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2
resulting in its degradation and allowing the release of
IL-1.alpha.. In human cells caspase-1 may also control the
processing and secretion of IL-37. A number of other caspase-1
substrates such as components of the cytoskeleton and glycolysis
pathway may contribute to caspase-1-dependent inflammation.
[0005] NLRP3-dependent ASC specks are released into the
extracellular environment where they can activate caspase-1, induce
processing of caspase-1 substrates and propagate inflammation.
[0006] Active cytokines derived from NLRP3 inflammasome activation
are important drivers of inflammation and interact with other
cytokine pathways to shape the immune response to infection and
injury. For example, IL-1.beta. signalling induces the secretion of
the pro-inflammatory cytokines IL-6 and TNF. IL-1.beta. and IL-18
synergise with IL-23 to induce IL-17 production by memory CD4 Th17
cells and by .gamma..delta. T cells in the absence of T cell
receptor engagement. IL-18 and IL-12 also synergise to induce
IFN-.gamma. production from memory T cells and NK cells driving a
Th1 response.
[0007] The inherited CAPS diseases Muckle-Wells syndrome (MWS),
familial cold autoinflammatory syndrome (FCAS) and neonatal-onset
multisystem inflammatory disease (NOMID) are caused by
gain-of-function mutations in NLRP3, thus defining NLRP3 as a
critical component of the inflammatory process. NLRP3 has also been
implicated in the pathogenesis of a number of complex diseases,
notably including metabolic disorders such as type 2 diabetes,
atherosclerosis, obesity and gout.
[0008] A role for NLRP3 in diseases of the central nervous system
is emerging, and lung diseases have also been shown to be
influenced by NLRP3. Furthermore, NLRP3 has a role in the
development of liver disease, kidney disease and aging. Many of
these associations were defined using Nlrp3-/- mice, but there have
also been insights into the specific activation of NLRP3 in these
diseases. In type 2 diabetes mellitus (T2D), the deposition of
islet amyloid polypeptide in the pancreas activates NLRP3 and
IL-1.beta. signaling, resulting in cell death and inflammation.
[0009] Several small molecules have been shown to inhibit the NLRP3
inflammasome. Glyburide inhibits IL-1.beta. production at
micromolar concentrations in response to the activation of NLRP3
but not NLRC4 or NLRP1. Other previously characterised weak NLRP3
inhibitors include parthenolide,
3,4-methylenedioxy-.beta.-nitrostyrene and dimethyl sulfoxide
(DMSO), although these agents have limited potency and are
nonspecific.
[0010] Current treatments for NLRP3-related diseases include
biologic agents that target IL-1. These are the recombinant IL-1
receptor antagonist anakinra, the neutralizing IL-1.beta. antibody
canakinumab and the soluble decoy IL-1 receptor rilonacept. These
approaches have proven successful in the treatment of CAPS, and
these biologic agents have been used in clinical trials for other
IL-1.beta.-associated diseases.
[0011] Some diarylsulfonylurea-containing compounds have been
identified as cytokine release inhibitory drugs (CRIDs) (Perregaux
et al.; J. Pharmacol. Exp. Ther. 299, 187-197, 2001). CRIDs are a
class of diarylsulfonylurea-containing compounds that inhibit the
post-translational processing of IL-1.beta.. Post-translational
processing of IL-1.beta. is accompanied by activation of caspase-1
and cell death. CRIDs arrest activated monocytes so that caspase-1
remains inactive and plasma membrane latency is preserved.
[0012] Certain sulfonylurea-containing compounds are also disclosed
as inhibitors of NLRP3 (see for example, Baldwin et al., J. Med.
Chem., 59(5), 1691-1710, 2016; and WO 2016/131098 A1, WO
2017/129897 A1, WO 2017/140778 A1, WO 2017/184604 A1, WO
2017/184623 A1, WO 2017/184624 A1, WO 2018/015445 A1 and WO
2018/136890 A1).
[0013] There is a need to provide compounds with improved
pharmacological and/or physiological and/or physicochemical
properties and/or those that provide a useful alternative to known
compounds.
SUMMARY OF THE INVENTION
[0014] A first aspect of the invention provides a compound of
formula (I):
##STR00002##
[0015] wherein: [0016] Q is selected from O or S; [0017] R.sup.1 is
a saturated or unsaturated C.sub.1-C.sub.15 hydrocarbyl group,
wherein the hydrocarbyl group may be straight-chained or branched,
or be or include cyclic groups, wherein the hydrocarbyl group may
optionally be substituted, and wherein the atom of R.sup.1 which is
attached to the sulfur atom of the sulfonylurea group is not a ring
atom of a cyclic group; and [0018] R.sup.2 is a cyclic group
substituted at the .alpha.-position, wherein R.sup.2 may optionally
be further substituted.
[0019] In one embodiment the compound is not:
##STR00003##
[0020] In one embodiment the compound is not:
##STR00004##
[0021] In one embodiment the compound is not:
##STR00005##
[0022] In one embodiment the compound is not:
##STR00006##
[0023] In the context of the present specification, a "hydrocarbyl"
substituent group or a hydrocarbyl moiety in a substituent group
only includes carbon and hydrogen atoms but, unless stated
otherwise, does not include any heteroatoms, such as N, O or S, in
its carbon skeleton. A hydrocarbyl group/moiety may be saturated or
unsaturated (including aromatic), and may be straight-chained or
branched, or be or include cyclic groups wherein, unless stated
otherwise, the cyclic group does not include any heteroatoms, such
as N, O or S, in its carbon skeleton. Examples of hydrocarbyl
groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl
and aryl groups/moieties and combinations of all of these
groups/moieties. Typically a hydrocarbyl group is a
C.sub.1-C.sub.12 hydrocarbyl group. More typically a hydrocarbyl
group is a C.sub.1-C.sub.10 hydrocarbyl group. A "hydrocarbylene"
group is similarly defined as a divalent hydrocarbyl group.
[0024] An "alkyl" substituent group or an alkyl moiety in a
substituent group may be straight-chained or branched. Examples of
alkyl groups/moieties include methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, t-butyl and n-pentyl groups/moieties. Unless
stated otherwise, the term "alkyl" does not include "cycloalkyl".
Typically an alkyl group is a C.sub.1-C.sub.12 alkyl group. More
typically an alkyl group is a C.sub.1-C.sub.6 alkyl group. An
"alkylene" group is similarly defined as a divalent alkyl
group.
[0025] An "alkenyl" substituent group or an alkenyl moiety in a
substituent group refers to an unsaturated alkyl group or moiety
having one or more carbon-carbon double bonds. Examples of alkenyl
groups/moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl,
1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl,
1,4-pentadienyl and 1,4-hexadienyl groups/moieties. Unless stated
otherwise, the term "alkenyl" does not include "cycloalkenyl".
Typically an alkenyl group is a C.sub.2-C.sub.12 alkenyl group.
More typically an alkenyl group is a C.sub.2-C.sub.6 alkenyl group.
An "alkenylene" group is similarly defined as a divalent alkenyl
group.
[0026] An "alkynyl" substituent group or an alkynyl moiety in a
substituent group refers to an unsaturated alkyl group or moiety
having one or more carbon-carbon triple bonds. Examples of alkynyl
groups/moieties include ethynyl, propargyl, but-1-ynyl and
but-2-ynyl. Typically an alkynyl group is a C.sub.2-C.sub.12
alkynyl group. More typically an alkynyl group is a C.sub.2-C.sub.6
alkynyl group. An "alkynylene" group is similarly defined as a
divalent alkynyl group.
[0027] A "cyclic" substituent group or a cyclic moiety in a
substituent group refers to any hydrocarbyl ring, wherein the
hydrocarbyl ring may be saturated or unsaturated (including
aromatic) and may include one or more heteroatoms, e.g. N, O or S,
in its carbon skeleton. Examples of cyclic groups include
cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl groups
as discussed below. A cyclic group may be monocyclic, bicyclic
(e.g. bridged, fused or spiro), or polycyclic. Typically, a cyclic
group is a 3- to 12-membered cyclic group, which means it contains
from 3 to 12 ring atoms. More typically, a cyclic group is a 3- to
7-membered monocyclic group, which means it contains from 3 to 7
ring atoms.
[0028] A "heterocyclic" substituent group or a heterocyclic moiety
in a substituent group refers to a cyclic group or moiety including
one or more carbon atoms and one or more (such as one, two, three
or four) heteroatoms, e.g. N, O or S, in the ring structure.
Examples of heterocyclic groups include heteroaryl groups as
discussed below and non-aromatic heterocyclic groups such as
azetinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl,
imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl,
tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl and
thiomorpholinyl groups, typically such as azetidinyl, azetinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and
thiomorpholinyl groups.
[0029] A "cycloalkyl" substituent group or a cycloalkyl moiety in a
substituent group refers to a saturated hydrocarbyl ring
containing, for example, from 3 to 7 carbon atoms, examples of
which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Unless stated otherwise, a cycloalkyl substituent group or moiety
may include monocyclic, bicyclic or polycyclic hydrocarbyl
rings.
[0030] A "cycloalkenyl" substituent group or a cycloalkenyl moiety
in a substituent group refers to a non-aromatic unsaturated
hydrocarbyl ring having one or more carbon-carbon double bonds and
containing, for example, from 3 to 7 carbon atoms, examples of
which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl and
cyclohex-1,3-dien-1-yl. Unless stated otherwise, a cycloalkenyl
substituent group or moiety may include monocyclic, bicyclic or
polycyclic hydrocarbyl rings.
[0031] An "aryl" substituent group or an aryl moiety in a
substituent group refers to an aromatic hydrocarbyl ring. The term
"aryl" includes monocyclic aromatic hydrocarbons and polycyclic
fused ring aromatic hydrocarbons wherein all of the fused ring
systems (excluding any ring systems which are part of or formed by
optional substituents) are aromatic. Examples of aryl
groups/moieties include phenyl, naphthyl, anthracenyl and
phenanthrenyl. Unless stated otherwise, the term "aryl" does not
include "heteroaryl".
[0032] A "heteroaryl" substituent group or a heteroaryl moiety in a
substituent group refers to an aromatic heterocyclic group or
moiety. The term "heteroaryl" includes monocyclic aromatic
heterocycles and polycyclic fused ring aromatic heterocycles
wherein all of the fused ring systems (excluding any ring systems
which are part of or formed by optional substituents) are aromatic.
Examples of heteroaryl groups/moieties include the following:
##STR00007##
[0033] wherein G=O, S or NH.
[0034] For the purposes of the present specification, where a
combination of moieties is referred to as one group, for example,
arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or
alkynylaryl, the last mentioned moiety contains the atom by which
the group is attached to the rest of the molecule. An example of an
arylalkyl group is benzyl. For the purposes of the present
specification, in an optionally substituted group or moiety:
[0035] (i) each hydrogen atom may optionally be replaced by a group
independently selected from halo; --CN; --NO.sub.2; --N.sub.3;
--R.sup..beta.; --OH; --OR.sup..beta.; --R.sup..alpha.-halo;
--R.sup..alpha.--CN; --R.sup..alpha.--NO.sub.2;
--R.sup..alpha.--N.sub.3; --R.sup..alpha.--R.sup..beta.;
--R.sup..alpha.--OH; --R.sup..alpha.--OR.sup..beta.; --SH;
--SR.sup..beta.; --SOR.sup..beta.; --SO.sub.2H;
--SO.sub.2R.sup..beta.; --SO.sub.2NH.sub.2;
--SO.sub.2NHR.sup..beta.; --SO.sub.2N(R.sup..beta.).sub.2;
--R.sup..alpha.--SH; --R.sup..alpha.--SR.sup..beta.;
--R.sup..alpha.--SOR.sup..beta.; --R.sup..alpha.--SO.sub.2H;
--R.sup..alpha.--SO.sub.2R.sup..beta.;
--R.sup..alpha.--SO.sub.2NH.sub.2;
--R.sup..alpha.--SO.sub.2NHR.sup..beta.;
--R.sup..alpha.--SO.sub.2N(R.sup..beta.).sub.2;
--Si(R.sup..beta.).sub.3; --O--Si(R).sub.3;
--R.sup..alpha.--Si(R.sup..beta.).sub.3;
--R.sup..alpha.--O--Si(R.sup..beta.).sub.3; --NH.sub.2;
--R.sup..alpha.--N+(R.sup..beta.).sub.3-CHO; --COR.sup..beta.;
--COOH; --COOR.sup..beta.; --OCOR.sup..beta.; --R.sup..alpha.--CHO;
--R.sup..alpha.--COR.sup..beta.; --R.sup..alpha.--COOH;
--R.sup..alpha.--COOR.sup..beta.; --R.sup..alpha.--OCOR.sup..beta.;
--C(.dbd.NH)R; --C(.dbd.NH)NH.sub.2; --C(.dbd.NH)NHR.sup..beta.;
--C(.dbd.NH)N(R.sup..beta.).sub.2;
--C(.dbd.NR.sup..beta.)R.sup..beta.;
--C(.dbd.NR.sup..beta.)NHR.sup..beta.;
--C(.dbd.NR.sup..beta.)N(R.sup..beta.).sub.2;
--C(.dbd.NOH)R.sup..beta.; --C(N.sub.2)R.sup..beta.;
--R.sup..alpha.--C(.dbd.NH)R.sup..beta.;
--R.sup..alpha.--C(.dbd.NH)NH.sub.2;
--R.sup..alpha.--C(.dbd.NH)NHR.sup..beta.;
--R.sup..alpha.--C(.dbd.NH)N(R.sup..beta.).sub.2;
--R.sup..alpha.--C(.dbd.NR.sup..beta.)R.sup..beta.;
--R.sup..alpha.--C(.dbd.NR.sup..beta.)NHR.sup..beta.;
--R.sup..alpha.--C(.dbd.NR.sup..beta.)N(R.sup..beta.).sub.2;
--R.sup..alpha.--C(.dbd.NOH)R.sup..beta.;
--R.sup..alpha.--C(N.sub.2)R; --NH--CHO; --NR.sup..beta.--CHO;
--NH--COR.sup..beta.; --NR.sup..beta.--COR.sup..beta.;
--CONH.sub.2; --CONHR.sup..beta.; --CON(R.sup..beta.).sub.2;
--R.sup..alpha.--NH--CHO; --R.sup..alpha.--NR.sup..beta.--CHO;
--R.sup..alpha.--NH--COR.sup..beta.;
--R.sup..alpha.--NR.sup..beta.--COR.sup..beta.;
--R.sup..alpha.--CONH.sub.2; --R.sup..alpha.--CONHR.sup..beta.;
--R.sup..alpha.--CON(R.sup..beta.).sub.2; --O--R.sup..alpha.--OH;
--O--R.sup..alpha.--OR.sup..beta.; --O--R.sup..alpha.--NH.sub.2;
--O--R.sup..alpha.--NHR.sup..beta.;
--O--R.sup..alpha.--N(R.sup..beta.).sub.2;
--O--R.sup..alpha.--N(O)(R.sup..beta.).sub.2;
--O--R.sup..alpha.--N.sup.+(R.sup..beta.).sub.3;
--NH--R.sup..alpha.--OH; --NH--R.sup..alpha.--OR.sup..beta.;
--NH--R.sup..alpha.--NH.sub.2; --NH--R.sup..alpha.--NHR.sup..beta.;
--NH--R.sup..alpha.--N(R.sup..beta.).sub.2;
--NH--R.sup..alpha.--N(O)(R.sup..beta.).sub.2;
--NH--R.sup..alpha.--N.sup.+(R.sup..beta.).sub.3;
--NR.sup..beta.--R.sup.+--OH;
--NR.sup..beta.--R.sup..alpha.--OR.sup..beta.;
--NR.sup..beta.--R.sup..alpha.--NH.sub.2;
--NR.sup..beta.--R.sup..alpha.--NHR.sup..beta.;
--NR.sup..beta.--R.sup..alpha.--N(R.sup..beta.).sub.2;
--NR.sup..beta.--R.sup..alpha.--N(O)(R.sup..beta.).sub.2;
--NR.sup..beta.--R.sup..alpha.--N.sup.+(R.sup..beta.).sub.3;
--N(O)R.sup..beta.--R.sup..alpha.--OH;
--N(O)R.sup..beta.--R.sup..alpha.--OR.sup..beta.;
--N(O)R.sup..beta.--R.sup..alpha.--NH.sub.2;
--N(O)R.sup..beta.--R.sup..alpha.--NHR.sup..beta.;
--N(O)R.sup..beta.--R.sup..alpha.--N(R.sup..beta.).sub.2;
--N(O)R.sup..beta.--R.sup..alpha.--N(O)(R).sub.2;
--N(O)R.sup..beta.--R.sup..alpha.--N.sup.+(R.sup..beta.).sub.3;
--N.sup.+(R.sup..beta.).sub.2--R.sup..alpha.--OH;
--N.sup.+(R.sup..beta.).sub.2--R.sup..alpha.--OR.sup..beta.;
--N.sup.+(R.sup..beta.).sub.2--R.sup..alpha.--NH.sub.2;
--N.sup.+(R.sup..beta.).sub.2--R.sup..alpha.--NHR.sup..beta.;
--N.sup.+(R.sup..beta.).sub.2--R.sup..alpha.--N(R.sup..beta.).sub.2;
or
--N.sup.+(R.sup..beta.).sub.2-R.sup..alpha.--N(O)(R.sup..beta.).sub.2;
and/or
[0036] (ii) any two hydrogen atoms attached to the same atom may
optionally be replaced by a .pi.-bonded substituent independently
selected from oxo (.dbd.O), .dbd.S, .dbd.NH or .dbd.NR.sup..beta.;
and/or
[0037] (iii) any two hydrogen atoms attached to the same or
different atoms, within the same optionally substituted group or
moiety, may optionally be replaced by a bridging substituent
independently selected from --O--, --S--, --NH--, --N.dbd.N--,
--N(R.sup..beta.)--, --N(O)(R.sup..beta.)--,
--N.sup.+(R.sup..beta.).sub.2- or --R.sup..alpha.--; [0038] wherein
each --R.sup..alpha.-- is independently selected from an alkylene,
alkenylene or alkynylene group, wherein the alkylene, alkenylene or
alkynylene group contains from 1 to 6 atoms in its backbone,
wherein one or more carbon atoms in the backbone of the alkylene,
alkenylene or alkynylene group may optionally be replaced by one or
more heteroatoms N, O or S, wherein one or more --CH.sub.2-- groups
in the backbone of the alkylene, alkenylene or alkynylene group may
optionally be replaced by one or more --N(O)(R.sup..beta.)-- or
--N.sup.+(R.sup..beta.).sub.2-- groups, and wherein the alkylene,
alkenylene or alkynylene group may optionally be substituted with
one or more halo and/or --R.sup..beta. groups; and [0039] wherein
each --R.sup..beta. is independently selected from a
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl or C.sub.2-C.sub.6 cyclic group, or wherein any two or
three --R.sup..beta. attached to the same nitrogen atom may,
together with the nitrogen atom to which they are attached, form a
C.sub.2-C.sub.7 cyclic group, and wherein any --R.sup..beta. may
optionally be substituted with one or more C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.3-C.sub.7 halocycloalkyl, --O(C.sub.1-C.sub.4 alkyl),
--O(C.sub.1-C.sub.4 haloalkyl), --O(C.sub.3-C.sub.7 cycloalkyl),
--O(C.sub.3-C.sub.7 halocycloalkyl), --CO(C.sub.1-C.sub.4 alkyl),
--CO(C.sub.1-C.sub.4 haloalkyl), --COO(C.sub.1-C.sub.4 alkyl),
--COO(C.sub.1-C.sub.4 haloalkyl), halo, --OH, --NH.sub.2, --CN,
--C.ident.CH, oxo (.dbd.O), or 4- to 6-membered heterocyclic
group.
[0040] Typically, the compounds of the present invention comprise
at most one quaternary ammonium group such as
--N.sup.+(R.sup..beta.).sub.3 or
--N.sup.+(R.sup..beta.).sub.2--.
[0041] Where reference is made to a
--R.sup..alpha.--C(N.sub.2)R.sup..beta. group, what is intended
is:
##STR00008##
[0042] Typically, in an optionally substituted group or moiety:
[0043] (i) each hydrogen atom may optionally be replaced by a group
independently selected from halo; --CN; --NO.sub.2; --N.sub.3;
--R.sup..beta.; --OH; --OR.sup..beta.; --SH; --SR.sup..beta.;
--SOR.sup..beta.; --SO.sub.2H; --SO.sub.2R.sup..beta.;
--SO.sub.2NH.sub.2; --SO.sub.2NHR.sup..beta.;
--SO.sub.2N(R.sup..beta.).sub.2; --R.sup..alpha.--SH;
--R.sup..alpha.--SR.sup..beta.; --R.sup..alpha.--SOR.sup..beta.;
--R.sup..alpha.--SO.sub.2H; --R.sup..alpha.--SO.sub.2R.sup..beta.;
--R.sup..alpha.--SO.sub.2NH.sub.2;
--R.sup..alpha.--SO.sub.2NHR.sup..beta.;
--R.sup..alpha.--SO.sub.2N(R.sup..beta.).sub.2; --NH.sub.2;
--NHR.sup..beta.; --N(R.sup..beta.).sub.2;
--R.sup..alpha.--NH.sub.2; --R.sup..alpha.--NHR.sup..beta.;
--R.sup..alpha.--N(R.sup..beta.).sub.2; --CHO; --CORP; --COOH;
--COOR.sup..beta.; --OCOR.sup..beta.; --R.sup..alpha.--CHO;
--R.sup..alpha.--COR.sup..beta.; --R.sup..alpha.--COOH;
--R.sup..alpha.--COOR.sup..beta.; --R.sup..alpha.--OCOR.sup..beta.;
--NH--CHO; --NR.sup..beta.--CHO; --NH--COR.sup..beta.;
--NR.sup..beta.--COR.sup..beta.; --CONH.sub.2; --CONHR.sup..beta.;
--CON(R).sub.2; --R.sup..alpha.--NH--CHO;
--R.sup..alpha.--NR.sup..beta.--CHO;
--R.sup..alpha.--NH--COR.sup..beta.;
--R.sup..alpha.--NR.sup..beta.--COR.sup..beta.;
--R.sup..alpha.--CONH.sub.2; --R.sup..alpha.--CONHR.sup..beta.;
--R.sup..alpha.--CON(R.sup..beta.).sub.2; --O--R.sup..alpha.--OH;
--O--R.sup..alpha.--OR.sup..beta.; --O--R.sup..alpha.--NH.sub.2;
--O--R.sup..alpha.--NHR.sup..beta.;
--O--R.sup..alpha.--N(R.sup..beta.).sub.2; --NH--R.sup..alpha.--OH;
--NH--R.sup..alpha.--OR.sup..beta.; --NH--R.sup..alpha.--NH.sub.2;
--NH--R.sup..alpha.--NHR.sup..beta.;
--NH--R.sup..alpha.--N(R).sub.2;
--NR.sup..beta.--R.sup..alpha.--OH;
--NR.sup..beta.--R.sup..alpha.--OR.sup..beta.;
--NR.sup..beta.--R.sup..alpha.--NH.sub.2;
--NR.sup..beta.--R.sup..alpha.--NHR.sup..beta.; or
--NR.sup..beta.--R.sup..alpha.--N(R.sup..beta.).sub.2; and/or
[0044] (ii) any two hydrogen atoms attached to the same carbon atom
may optionally be replaced by a .pi.-bonded substituent
independently selected from oxo (.dbd.O), .dbd.S, .dbd.NH or
.dbd.NR; and/or
[0045] (iii) any two hydrogen atoms attached to the same or
different atoms, within the same optionally substituted group or
moiety, may optionally be replaced by a bridging substituent
independently selected from --O--, --S--, --NH--,
--N(R.sup..beta.)-- or --R.sup..alpha.--; [0046] wherein each
--R.sup..alpha.-- is independently selected from an alkylene,
alkenylene or alkynylene group, wherein the alkylene, alkenylene or
alkynylene group contains from 1 to 6 atoms in its backbone,
wherein one or more carbon atoms in the backbone of the alkylene,
alkenylene or alkynylene group may optionally be replaced by one or
more heteroatoms N, O or S, and wherein the alkylene, alkenylene or
alkynylene group may optionally be substituted with one or more
halo and/or --R.sup..beta. groups; and [0047] wherein each
--R.sup..beta. is independently selected from a C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or
C.sub.2-C.sub.6 cyclic group, and wherein any --R.sup..beta. may
optionally be substituted with one or more C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl,
--O(C.sub.1-C.sub.4 alkyl), --O(C.sub.1-C.sub.4 haloalkyl),
--O(C.sub.3-C.sub.7 cycloalkyl), halo, --OH, --NH.sub.2, --CN,
--C.ident.CH or oxo (.dbd.O) groups.
[0048] Typically, in an optionally substituted group or moiety:
[0049] (i) each hydrogen atom may optionally be replaced by a group
independently selected from halo; --CN; --NO.sub.2; --N.sub.3;
--R.sup..beta.; --OH; --OR.sup..beta.; --SH; --SR.sup..beta.;
--SOR.sup..beta.; --SO.sub.2H; --SO.sub.2R.sup..beta.;
--SO.sub.2NH.sub.2; --SO.sub.2NHR.sup..beta.;
--SO.sub.2N(R.sup..beta.).sub.2; --R.sup..alpha.--SH;
--R.sup..alpha.--SR.sup..beta.; --R.sup..alpha.--SOR.sup..beta.;
--R.sup..alpha.--SO.sub.2H; --R.sup..alpha.--SO.sub.2R.sup..beta.;
--R.sup..alpha.--SO.sub.2NH.sub.2;
--R.sup..alpha.--SO.sub.2NHR.sup..beta.;
--R.sup..alpha.--SO.sub.2N(R.sup..beta.).sub.2; --NH.sub.2;
--NHR.sup..beta.; --N(R.sup..beta.).sub.2;
--R.sup..alpha.--NH.sub.2; --R.sup..alpha.--NHR.sup..beta.;
--R.sup..alpha.--N(R.sup..beta.).sub.2; --CHO; --COR.sup..beta.;
--COOH; --COOR.sup..beta.; --OCOR.sup..beta.; --R.sup..alpha.--CHO;
--R.sup..alpha.--COR.sup..beta.; --R.sup..alpha.--COOH;
--R.sup..alpha.--COOR.sup..beta.; or
--R.sup..alpha.--OCOR.sup..beta.; and/or
[0050] (ii) any two hydrogen atoms attached to the same carbon atom
may optionally be replaced by a .pi.-bonded substituent
independently selected from oxo (.dbd.O), .dbd.S, .dbd.NH or
.dbd.NR.sup..beta.; and/or
[0051] (iii) any two hydrogen atoms attached to the same or
different atoms, within the same optionally substituted group or
moiety, may optionally be replaced by a bridging substituent
independently selected from --O--, --S--, --NH--,
--N(R.sup..beta.)-- or --R.sup..alpha.--; [0052] wherein each
--R.sup..alpha.-- is independently selected from an alkylene,
alkenylene or alkynylene group, wherein the alkylene, alkenylene or
alkynylene group contains from 1 to 6 atoms in its backbone,
wherein one or more carbon atoms in the backbone of the alkylene,
alkenylene or alkynylene group may optionally be replaced by one or
more heteroatoms N, O or S, and wherein the alkylene, alkenylene or
alkynylene group may optionally be substituted with one or more
halo and/or --R.sup..beta. groups; and [0053] wherein each
--R.sup..beta. is independently selected from a C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or
C.sub.2-C.sub.6 cyclic group, and wherein any --R.sup..beta. may
optionally be substituted with one or more C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl,
--O(C.sub.1-C.sub.4 alkyl), --O(C.sub.1-C.sub.4 haloalkyl),
--O(C.sub.3-C.sub.7 cycloalkyl), halo, --OH, --NH.sub.2, --CN,
--C.ident.C or oxo (.dbd.O) groups.
[0054] Typically, in an optionally substituted group or moiety:
[0055] (i) each hydrogen atom may optionally be replaced by a group
independently selected from halo; --CN; --NO.sub.2; --N.sub.3;
--R.sup..beta.; --OH; --OR.sup..beta.; --SH; --SR.sup..beta.;
--SOR.sup..beta.; --SO.sub.2H; --SO.sub.2R.sup..beta.;
--SO.sub.2NH.sub.2; --SO.sub.2NHR.sup..beta.;
--SO.sub.2N(R.sup..beta.).sub.2; --R.sup..alpha.--SH;
--R.sup..alpha.--SR.sup..beta.; --R.sup..alpha.--SOR.sup..beta.;
--R.sup..alpha.--SO.sub.2H; --R.sup..alpha.--SO.sub.2R.sup..beta.;
--R.sup..alpha.--SO.sub.2NH.sub.2;
--R.sup..alpha.--SO.sub.2NHR.sup..beta.;
--R.sup..alpha.--SO.sub.2N(R.sup..beta.).sub.2; --NH.sub.2;
--NHR.sup..beta.; --N(R.sup..beta.).sub.2;
--R.sup..alpha.--NH.sub.2; --R.sup..alpha.--NHR.sup..beta.;
--R.sup..alpha.--N(R.sup..beta.).sub.2; --CHO; --COR.sup..beta.;
--COOH; --COOR.sup..beta.; --OCOR.sup..beta.; --R.sup..alpha.--CHO;
--R.sup..alpha.--COR.sup..beta.; --R.sup..alpha.--COOH;
--R.sup..alpha.--COOR.sup..beta.; or
--R.sup..alpha.--OCOR.sup..beta.; and/or
[0056] (ii) any two hydrogen atoms attached to the same carbon atom
may optionally be replaced by a .pi.-bonded substituent
independently selected from oxo (.dbd.O), .dbd.S, .dbd.NH or
.dbd.NR.sup..beta.; and/or
[0057] (iii) any two hydrogen atoms attached to the same or
different atoms, within the same optionally substituted group or
moiety, may optionally be replaced by a bridging substituent
independently selected from --O--, --S--, --NH--,
--N(R.sup..beta.)-- or --R.sup..alpha.--; [0058] wherein each
--R.sup..alpha.-- is independently selected from an alkylene,
alkenylene or alkynylene group, wherein the alkylene, alkenylene or
alkynylene group contains from 1 to 6 atoms in its backbone,
wherein one or more carbon atoms in the backbone of the alkylene,
alkenylene or alkynylene group may optionally be replaced by one or
more heteroatoms N, O or S, and wherein the alkylene, alkenylene or
alkynylene group may optionally be substituted with one or more
halo and/or --R.sup..beta. groups; and [0059] wherein each
--R.sup..beta. is independently selected from a C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or
C.sub.2-C.sub.6 cyclic group, and wherein any --R.sup..beta. may
optionally be substituted with one or more C.sub.1-C.sub.4 alkyl or
halo groups.
[0060] Typically a substituted group comprises 1, 2, 3 or 4
substituents, more typically 1, 2 or 3 substituents, more typically
1 or 2 substituents, and more typically 1 substituent.
[0061] Unless stated otherwise, any divalent bridging substituent
(e.g. --O--, --S--, --NH--, --N(R.sup..beta.)--,
--N(O)(R.sup..beta.)--, --N.sup.+(R.sup..beta.).sub.2- or
--R.sup..alpha.--) of an optionally substituted group or moiety
(e.g. R.sup.1) must only be attached to the specified group or
moiety and may not be attached to a second group or moiety (e.g.
R.sup.2), even if the second group or moiety can itself be
optionally substituted.
[0062] The term "halo" includes fluoro, chloro, bromo and iodo.
[0063] Unless stated otherwise, where a group is prefixed by the
term "halo", such as a haloalkyl or halomethyl group, it is to be
understood that the group in question is substituted with one or
more halo groups independently selected from fluoro, chloro, bromo
and iodo. Typically, the maximum number of halo substituents is
limited only by the number of hydrogen atoms available for
substitution on the corresponding group without the halo prefix.
For example, a halomethyl group may contain one, two or three halo
substituents. A haloethyl or halophenyl group may contain one, two,
three, four or five halo substituents. Similarly, unless stated
otherwise, where a group is prefixed by a specific halo group, it
is to be understood that the group in question is substituted with
one or more of the specific halo groups. For example, the term
"fluoromethyl" refers to a methyl group substituted with one, two
or three fluoro groups.
[0064] Unless stated otherwise, where a group is said to be
"halo-substituted", it is to be understood that the group in
question is substituted with one or more halo groups independently
selected from fluoro, chloro, bromo and iodo. Typically, the
maximum number of halo substituents is limited only by the number
of hydrogen atoms available for substitution on the group said to
be halo-substituted. For example, a halo-substituted methyl group
may contain one, two or three halo substituents. A halo-substituted
ethyl or halo-substituted phenyl group may contain one, two, three,
four or five halo substituents.
[0065] Unless stated otherwise, any reference to an element is to
be considered a reference to all isotopes of that element. Thus,
for example, unless stated otherwise any reference to hydrogen is
considered to encompass all isotopes of hydrogen including
deuterium and tritium.
[0066] Where reference is made to a hydrocarbyl or other group
including one or more heteroatoms N, O or S in its carbon skeleton,
or where reference is made to a carbon atom of a hydrocarbyl or
other group being replaced by an N, O or S atom, what is intended
is that:
##STR00009##
is replaced by
##STR00010## [0067] --CH.sub.2-- is replaced by --NH--, --O-- or
--S--; [0068] --CH.sub.3 is replaced by --NH.sub.2, --OH or --SH;
[0069] --CH.dbd. is replaced by --N.dbd.; [0070] CH.sub.2.dbd. is
replaced by NH.dbd., O.dbd. or S.dbd.; or [0071] CH.ident. is
replaced by N--;
[0072] provided that the resultant group comprises at least one
carbon atom. For example, methoxy, dimethylamino and aminoethyl
groups are considered to be hydrocarbyl groups including one or
more heteroatoms N, O or S in their carbon skeleton.
[0073] Where reference is made to a --CH.sub.2-- group in the
backbone of a hydrocarbyl or other group being replaced by a
--N(O)(R.sup..beta.)-- or --N.sup.+(R.sup..beta.).sub.2-- group,
what is intended is that: [0074] --CH.sub.2-- is replaced by
##STR00011##
[0074] or [0075] CH.sub.2-- is replaced by
##STR00012##
[0076] In the context of the present specification, unless
otherwise stated, a C.sub.x-C.sub.y group is defined as a group
containing from x to y carbon atoms. For example, a C.sub.1-C.sub.4
alkyl group is defined as an alkyl group containing from 1 to 4
carbon atoms. Optional substituents and moieties are not taken into
account when calculating the total number of carbon atoms in the
parent group substituted with the optional substituents and/or
containing the optional moieties. For the avoidance of doubt,
replacement heteroatoms, e.g. N, O or S, are counted as carbon
atoms when calculating the number of carbon atoms in a
C.sub.x-C.sub.y group. For example, a morpholinyl group is to be
considered a C.sub.6 heterocyclic group, not a C.sub.4 heterocyclic
group.
[0077] For the purposes of the present specification, where it is
stated that a first atom or group is "directly attached" to a
second atom or group it is to be understood that the first atom or
group is covalently bonded to the second atom or group with no
intervening atom(s) or groups being present. So, for example, for
the group (C.dbd.O)N(CH.sub.3).sub.2, the carbon atom of each
methyl group is directly attached to the nitrogen atom and the
carbon atom of the carbonyl group is directly attached to the
nitrogen atom, but the carbon atom of the carbonyl group is not
directly attached to the carbon atom of either methyl group.
[0078] R.sup.1 is a saturated or unsaturated C.sub.1-C.sub.15
hydrocarbyl group. For the avoidance of doubt, it is noted that the
atom of R.sup.1 which is attached to the sulfur atom of the
sulfonylurea group is a carbon atom.
[0079] R.sup.1 is a saturated or unsaturated C.sub.1-C.sub.15
hydrocarbyl group, wherein the hydrocarbyl group may optionally be
substituted. In one embodiment, R.sup.1 is a saturated or
unsaturated C.sub.1-C.sub.12 hydrocarbyl group, wherein the
hydrocarbyl group may optionally be substituted. In another
embodiment, R.sup.1 is a saturated or unsaturated C.sub.1-C.sub.10
hydrocarbyl group, wherein the hydrocarbyl group may optionally be
substituted. In another embodiment, R.sup.1 is a saturated or
unsaturated C.sub.1-C.sub.9 hydrocarbyl group, wherein the
hydrocarbyl group may optionally be substituted. In another
embodiment, R.sup.1 is a saturated or unsaturated C.sub.1-C.sub.8
hydrocarbyl group, wherein the hydrocarbyl group may optionally be
substituted. In another embodiment, R.sup.1 is a saturated or
unsaturated C.sub.1-C.sub.7 hydrocarbyl group, wherein the
hydrocarbyl group may optionally be substituted.
[0080] In one embodiment, R.sup.1 is a branched C.sub.3-C.sub.15
alkyl group, wherein the alkyl group may optionally be substituted.
In one embodiment, R.sup.1 is a branched C.sub.3-C.sub.12 alkyl
group, wherein the alkyl group may optionally be substituted. In
another embodiment, R.sup.1 is a branched C.sub.3-C.sub.10 alkyl
group, wherein the alkyl group may optionally be substituted. In
another embodiment, R.sup.1 is a branched C.sub.3-C.sub.9 alkyl
group, wherein the alkyl group may optionally be substituted. In
another embodiment, R.sup.1 is a branched C.sub.3-C.sub.8 alkyl
group, wherein the alkyl group may optionally be substituted. In
another embodiment, R.sup.1 is a branched C.sub.3-C.sub.7 alkyl
group, wherein the alkyl group may optionally be substituted. For
example, R.sup.1 may be an isopropyl, sec-butyl, isobutyl or
tert-butyl group, all of which may be unsubstituted or optionally
substituted.
[0081] In one embodiment, R.sup.1 is a straight-chained
C.sub.2-C.sub.15 alkenyl group, wherein any hydrogen atom directly
attached to a sp.sup.3 hybridised carbon atom of the alkenyl group
may optionally be substituted. In one embodiment, R.sup.1 is a
straight-chained C.sub.2-C.sub.12 alkenyl group, wherein any
hydrogen atom directly attached to a sp.sup.3 hybridised carbon
atom of the alkenyl group may optionally be substituted. In another
embodiment, R.sup.1 is a straight-chained C.sub.2-C.sub.10 alkenyl
group, wherein any hydrogen atom directly attached to a sp.sup.3
hybridised carbon atom of the alkenyl group may optionally be
substituted. In another embodiment, R.sup.1 is a straight-chained
C.sub.2-C.sub.9 alkenyl group, wherein any hydrogen atom directly
attached to a sp.sup.3 hybridised carbon atom of the alkenyl group
may optionally be substituted. In another embodiment, R.sup.1 is a
straight-chained C.sub.2-C.sub.8 alkenyl group, wherein any
hydrogen atom directly attached to a sp.sup.3 hybridised carbon
atom of the alkenyl group may optionally be substituted. In another
embodiment, R.sup.1 is a straight-chained C.sub.2-C.sub.7 alkenyl
group, wherein any hydrogen atom directly attached to a sp.sup.3
hybridised carbon atom of the alkenyl group may optionally be
substituted. For example, R.sup.1 may be a straight-chained
ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl,
1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl or 1,4-hexadienyl
group, all of which may be unsubstituted or, where possible,
optionally substituted at a sp.sup.3 carbon atom.
[0082] In one embodiment, --R.sup.1 is --(CH.sub.2).sub.nR.sup.3,
wherein n is 1, 2 or 3, and R.sup.3 is a branched or cyclic
C.sub.1-C.sub.(15-n) hydrocarbyl group, wherein the hydrocarbyl
group may optionally be substituted. In one embodiment, R.sup.3 is
a branched or cyclic C.sub.1-C.sub.(12-n) hydrocarbyl group,
wherein the hydrocarbyl group may optionally be substituted. In one
embodiment, R.sup.3 is a branched or cyclic C.sub.1-C.sub.(10-n)
hydrocarbyl group, wherein the hydrocarbyl group may optionally be
substituted. In one embodiment, R.sup.3 is a branched or cyclic
C.sub.1-C.sub.(9-n) hydrocarbyl group, wherein the hydrocarbyl
group may optionally be substituted. In one embodiment, R.sup.3 is
a branched or cyclic C.sub.1-C.sub.(8-n) hydrocarbyl group, wherein
the hydrocarbyl group may optionally be substituted. In one
embodiment, R.sup.3 is a branched or cyclic C.sub.1-C.sub.(7-n)
hydrocarbyl group, wherein the hydrocarbyl group may optionally be
substituted.
[0083] In another embodiment, --R.sup.1 is
--(CHR.sup.4).sub.nR.sup.3; wherein n is 1, 2 or 3; R.sup.4 is
independently selected from hydrogen, methyl or ethyl; and R.sup.3
is a branched or cyclic C.sub.1-C.sub.(12-n) hydrocarbyl group,
wherein the hydrocarbyl group may optionally be substituted with
one, two or three substituents independently selected from halo,
C.sub.1-C.sub.4 haloalkyl, --CN, --N.sub.3, --NO.sub.2, --OH,
--SR.sup..delta., --SOR.sup..delta., --SO.sub.2R.sup..delta.,
--SO.sub.2N(R.sup..delta.).sub.2, --NH.sub.2, --COR.sup..delta.,
--COOR.sup..delta. or --OCOR.sup..delta., wherein each
--R.sup..delta. is independently selected from hydrogen or a
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4
alkynyl, C.sub.1-C.sub.4 haloalkyl or C.sub.3-C.sub.7 cycloalkyl
group.
[0084] In yet another embodiment, --R.sup.1 is
--(CHR.sub.4).sub.nR.sup.3; wherein n is 1, 2 or 3; R.sup.4 is
independently selected from hydrogen, methyl or ethyl; and R.sup.3
is a branched or cyclic C.sub.1-C.sub.(10-n) hydrocarbyl group,
wherein the hydrocarbyl group may optionally be substituted with
one, two or three substituents independently selected from halo,
C.sub.1-C.sub.4 haloalkyl, --CN, --N.sub.3, --SR.sup..delta.,
--SOR.sup..delta., --SO.sub.2R.sup..delta. or
--SO.sub.2N(R.sup..delta.).sub.2, wherein each --R.sup..delta. is
independently selected from hydrogen or a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
haloalkyl or C.sub.3-C.sub.7 cycloalkyl group.
[0085] In a further embodiment, --R.sup.1 is
--(CHR.sup.4).sub.nR.sup.3; wherein n is 1, 2 or 3; R.sup.4 is
independently selected from hydrogen, methyl or ethyl; and R.sup.3
is phenyl optionally substituted with one, two or three
substituents independently selected from halo, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, --CN, --N.sub.3, --NO.sub.2,
--OR.sup..delta., --SR.sup..delta., --SOR.sup..delta.,
--SO.sub.2R.sup..delta., --SO.sub.2N(R.sup..delta.).sub.2,
--NH.sub.2, --COR.sup..delta., --COOR.sup..delta. or
--OCOR.sup..delta., wherein each --R.sup..delta. is independently
selected from hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl or
C.sub.3-C.sub.7 cycloalkyl group.
[0086] In one embodiment, --R.sup.1 is
--(C(R.sup.4).sub.2).sub.nR.sup.3; wherein n is 1, 2 or 3; each
R.sup.4 is independently selected from hydrogen, halo, methyl,
halomethyl, ethyl or haloethyl; and R.sup.3 is a cyclic
C.sub.3-C.sub.14 hydrocarbyl group, wherein the cyclic hydrocarbyl
group may optionally be halo substituted and/or may optionally be
substituted with one, two or three substituents independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
--CN, --N.sub.3, --NO.sub.2, --OR.sup..delta., --SR.sup..delta.,
--SOR.sup..delta., --SO.sub.2R.sup..delta.,
--SO.sub.2N(R.sup..delta.).sub.2, --N(R.sup..delta.).sub.2,
--COR.sup..delta., --COOR.sup..delta. or --OCOR.sup..delta.,
wherein each --R.sup..delta. is independently selected from
hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, or C.sub.3-C.sub.7 cycloalkyl group, all
of which may optionally be halo substituted, and wherein the group
--R.sup.1 including any optional substituents contains from 4 to 15
carbon atoms. Typically in such an embodiment, --R.sup.1 is
--(C(R.sup.4).sub.2).sub.nR.sup.3; wherein n is 1, 2 or 3; each
R.sup.4 is independently selected from hydrogen, halo, methyl,
halomethyl, ethyl or haloethyl; and R.sup.3 is a monocyclic
C.sub.3-C.sub.7 hydrocarbyl group, wherein the monocyclic
hydrocarbyl group may optionally be halo substituted and/or may
optionally be substituted with one, two or three substituents
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, --CN, --N.sub.3, --NO.sub.2, --OR.sup..delta.,
--N(R.sup..delta.).sub.2, --COR.sup..delta., --COOR.sup..delta. or
--OCOR.sup..delta., wherein each --R.sup..delta. is independently
selected from hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.3-C.sub.7
halocycloalkyl group, and wherein the group --R.sup.1 including any
optional substituents contains from 4 to 15 carbon atoms. More
typically, --R.sup.1 is --(C(R.sup.4).sub.2).sub.nR.sup.3; wherein
n is 1, 2 or 3; each R.sup.4 is independently selected from
hydrogen, halo, methyl, halomethyl, ethyl or haloethyl; and R.sup.3
is a phenyl group, wherein the phenyl group may optionally be halo
substituted and/or may optionally be substituted with one, two or
three substituents independently selected from C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, --CN, --NO.sub.2,
--OR.sup..delta., --N(R.sup..delta.).sub.2, --COR.sup..delta.,
--COOR.sup..delta. or --OCOR.sup..delta., wherein each
--R.sup..delta. is independently selected from hydrogen or a
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7
cycloalkyl or C.sub.3-C.sub.7 halocycloalkyl group, and wherein the
group --R.sup.1 including any optional substituents contains from 7
to 15 carbon atoms. More typically still, --R.sup.1 is
--(C(R.sup.4).sub.2).sub.nR.sup.3; wherein n is 1 or 2; each
R.sup.4 is independently selected from hydrogen, halo, methyl or
halomethyl; and R.sup.3 is a phenyl group, wherein the phenyl group
may optionally be halo substituted and/or may optionally be
substituted with one or two substituents independently selected
from C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, --CN,
--OR.sup..delta., --COR.sup..delta., or --COOR.sup..delta., wherein
each --R.sup..delta. is independently selected from hydrogen or a
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, cyclopropyl or
halocyclopropyl group, and wherein the group --R.sup.1 including
any optional substituents contains from 7 to 12 carbon atoms.
[0087] In one embodiment, R.sup.1 is substituted with one or more
substituents independently selected from halo, C.sub.1-C.sub.4
haloalkyl, --CN, --N.sub.3, --NO.sub.2, --OH, --SR.sup..delta.,
--SOR.sup..delta., --SO.sub.2R.sup..delta.,
--SO.sub.2N(R.sup..delta.).sub.2, --NH.sub.2, --COR.sup..delta.,
--COOR.sup.6 or --OCOR.sup..delta.; wherein each --R.sup..delta. is
independently selected from hydrogen or a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
haloalkyl or C.sub.3-C.sub.7 cycloalkyl group. With such
substituents, R.sup.1 may be a saturated or unsaturated
C.sub.1-C.sub.12 or C.sub.1-C.sub.10 or C.sub.1-C.sub.9 or
C.sub.1-C.sub.8 or C.sub.1-C.sub.7 or C.sub.1-C.sub.6 or
C.sub.1-C.sub.5 or C.sub.1-C.sub.4 hydrocarbyl group.
[0088] In one embodiment, R.sup.1 is substituted with one or more
substituents independently selected from halo, --CN, --NO.sub.2,
--OH, --SR.sup..delta., --SOR.sup..delta., --SO.sub.2R.sup..delta.,
--SO.sub.2N(R.sup..delta.).sub.2, --NH.sub.2, --COR.sup..delta.,
--COOR.sup.6 or --OCOR.sup..delta.; wherein each --R.sup..delta. is
independently selected from hydrogen or a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
haloalkyl or C.sub.3-C.sub.7 cycloalkyl group. With such
substituents, R.sup.1 may be a saturated or unsaturated
C.sub.1-C.sub.12 or C.sub.1-C.sub.10 or C.sub.1-C.sub.9 or
C.sub.1-C.sub.8 or C.sub.1-C.sub.7 or C.sub.1-C.sub.6 or
C.sub.1-C.sub.5 or C.sub.1-C.sub.4 hydrocarbyl group.
[0089] In another embodiment, R.sup.1 is substituted with one or
more substituents independently selected from halo, C.sub.1-C.sub.4
haloalkyl, --CN, --N.sub.3, --SR.sup..delta., --SOR.sup..delta.,
--SO.sub.2R.sup.6 or --SO.sub.2N(R).sub.2; wherein each --R.sup.6
is independently selected from hydrogen or a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
haloalkyl or C.sub.3-C.sub.7 cycloalkyl group. With such
substituents, R.sup.1 may be a saturated or unsaturated
C.sub.1-C.sub.12 or C.sub.1-C.sub.10 or C.sub.1-C.sub.9 or
C.sub.1-C.sub.8 or C.sub.1-C.sub.7 or C.sub.1-C.sub.6 or
C.sub.1-C.sub.5 or C.sub.1-C.sub.4 hydrocarbyl group.
[0090] In another embodiment, R.sup.1 is substituted with one or
more substituents independently selected from halo, --CN,
--SR.sup..delta., --SOR.sup..delta., --SO.sub.2R.sup.6 or
--SO.sub.2N(R.sup..delta.).sub.2; wherein each --R.sup..delta. is
independently selected from hydrogen or a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
haloalkyl or C.sub.3-C.sub.7 cycloalkyl group. With such
substituents, R.sup.1 may be a saturated or unsaturated
C.sub.1-C.sub.12 or C.sub.1-C.sub.10 or C.sub.1-C.sub.9 or
C.sub.1-C.sub.8 or C.sub.1-C.sub.7 or C.sub.1-C.sub.6 or
C.sub.1-C.sub.5 or C.sub.1-C.sub.4 hydrocarbyl group.
[0091] In another embodiment, R.sup.1 is substituted with one or
more substituents independently selected from --CN, --N.sub.3,
--SR.sup..delta., --SOR.sup..delta., --SO.sub.2R.sup.6 or
--SO.sub.2N(R.sup..delta.).sub.2; wherein each --R.sup..delta. is
independently selected from hydrogen or a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
haloalkyl or C.sub.3-C.sub.7 cycloalkyl group. With such
substituents, R.sup.1 may be a saturated or unsaturated
C.sub.1-C.sub.12 or C.sub.1-C.sub.10 or C.sub.1-C.sub.9 or
C.sub.1-C.sub.8 or C.sub.1-C.sub.7 or C.sub.1-C.sub.6 or
C.sub.1-C.sub.5 or C.sub.1-C.sub.4 hydrocarbyl group.
[0092] In another embodiment, R.sup.1 is substituted with one or
more substituents independently selected from --CN,
--SR.sup..delta., --SOR.sup..delta., --SO.sub.2R.sup..delta. or
--SO.sub.2N(R.sup..delta.).sub.2; wherein each --R.sup..delta. is
independently selected from hydrogen or a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
haloalkyl or C.sub.3-C.sub.7 cycloalkyl group. With such
substituents, R.sup.1 may be a saturated or unsaturated
C.sub.1-C.sub.12 or C.sub.1-C.sub.10 or C.sub.1-C.sub.9 or
C.sub.1-C.sub.8 or C.sub.1-C.sub.7 or C.sub.1-C.sub.6 or
C.sub.1-C.sub.5 or C.sub.1-C.sub.4 hydrocarbyl group.
[0093] In another embodiment, R.sup.1 is substituted with one or
more substituents independently selected from halo, C.sub.1-C.sub.4
haloalkyl, --CN or --N.sub.3. With such substituents, R.sup.1 may
be a saturated or unsaturated C.sub.1-C.sub.12 or C.sub.1-C.sub.10
or C.sub.1-C.sub.9 or C.sub.1-C.sub.8 or C.sub.1-C.sub.7 or
C.sub.1-C.sub.6 or C.sub.1-C.sub.5 or C.sub.1-C.sub.4 hydrocarbyl
group.
[0094] In another embodiment, R.sup.1 is substituted with one or
more substituents independently selected from halo or --CN. With
such substituents, R.sup.1 may be a saturated or unsaturated
C.sub.1-C.sub.12 or C.sub.1-C.sub.10 or C.sub.1-C.sub.9 or
C.sub.1-C.sub.8 or C.sub.1-C.sub.7 or C.sub.1-C.sub.6 or
C.sub.1-C.sub.5 or C.sub.1-C.sub.4 hydrocarbyl group.
[0095] In one embodiment, R.sup.1 is a C.sub.1-C.sub.15 hydrocarbyl
group, wherein the hydrocarbyl group is substituted with one or
more substituents independently selected from halo, --CN,
--N.sub.3, --NO.sub.2, --OR.sup..delta., --SR.sup..delta.,
--SOR.sup..delta., --SO.sub.2R.sup..delta.,
--SO.sub.2N(R.sup..delta.).sub.2, --N(R.sup..delta.).sub.2,
--COR.sup..delta., --COOR.sup..delta. or --OCOR.sup..delta.;
wherein each --R.sup..delta. is independently selected from
hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, or C.sub.3-C.sub.7 cycloalkyl group, all
of which may optionally be halo substituted. Typically in such an
embodiment, R.sup.1 is a straight-chained or branched
C.sub.1-C.sub.12 hydrocarbyl group, wherein the hydrocarbyl group
is substituted with one or more substituents independently selected
from halo, --CN, --N.sub.3, --NO.sub.2, --OR.sup..delta.,
--N(R.sup..delta.).sub.2, --COR.sup..delta., --COOR.sup..delta. or
--OCOR.sup..delta.; wherein each --R.sup..delta. is independently
selected from hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl, C.sub.2-C.sub.4 alkynyl, or C.sub.3-C.sub.7 cycloalkyl
group, all of which may optionally be halo substituted. More
typically in such an embodiment, R.sup.1 is a C.sub.1-C.sub.6 alkyl
or C.sub.2-C.sub.6 alkenyl group, wherein the alkyl or alkenyl
group is halo substituted and/or is substituted with one, two or
three substituents independently selected from --CN, --N.sub.3,
--NO.sub.2, --OR.sup..delta., --N(R.sup..delta.).sub.2,
--COR.sup..delta. or --COOR.sup..delta., wherein each
--R.sup..delta. is independently selected from hydrogen or a
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7
cycloalkyl or C.sub.3-C.sub.7 halocycloalkyl group. More typically
still, R.sup.1 is a C.sub.1-C.sub.6 alkyl group, wherein the alkyl
group is halo substituted and/or is substituted with one, two or
three substituents independently selected from --CN, --N.sub.3 or
--OR.sup..delta., wherein each --R.sup..delta. is independently
selected from hydrogen or a C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
haloalkyl, cyclopropyl or halocyclopropyl group.
[0096] In one aspect of any of the above embodiments, R.sup.1
contains from 1 to 25 atoms other than hydrogen. More typically,
R.sup.1 contains from 1 to 20 atoms other than hydrogen. More
typically, R.sup.1 contains from 1 to 15 atoms other than hydrogen.
More typically, R.sup.1 contains from 1 to 12 atoms other than
hydrogen. More typically, R.sup.1 contains from 1 to 10 atoms other
than hydrogen. More typically, R.sup.1 contains from 1 to 7 atoms
other than hydrogen.
[0097] R.sup.2 is a cyclic group substituted at the
.alpha.-position, wherein R.sup.2 may optionally be further
substituted. For the avoidance of doubt, it is noted that it is a
ring atom of the cyclic group of R.sup.2 that is directly attached
to the nitrogen atom of the urea or thiourea group, not any
substituent.
[0098] As used herein, the nomenclature .alpha., .beta., .alpha.',
.beta.' refers to the position of the atoms of a cyclic group, such
as --R.sup.2, relative to the point of attachment of the cyclic
group to the remainder of the molecule. For example, where
--R.sup.2 is a 1,2,3,5,6,7-hexahydro-s-indacen-4-yl moiety, the
.alpha., .beta., .alpha.' and .beta.' positions are as follows:
##STR00013##
[0099] For the avoidance of doubt, where it is stated that a cyclic
group, such as an aryl or a heteroaryl group, is substituted at the
.alpha. and/or .alpha.' positions, it is to be understood that one
or more hydrogen atoms at the .alpha. and/or .alpha.' positions
respectively are replaced by one or more substituents, such as any
optional substituent as defined above. Unless stated otherwise, the
term `substituted` does not include the replacement of one or more
ring carbon atoms by one or more ring heteroatoms.
[0100] In one embodiment of the first aspect of the invention,
R.sup.2 is an aryl or a heteroaryl group, wherein the aryl or the
heteroaryl group is substituted at the .alpha.-position, and
wherein R.sup.2 may optionally be further substituted. Typically,
R.sup.2 is a phenyl or a 5- or 6-membered heteroaryl group, wherein
the phenyl or the heteroaryl group is substituted at the
.alpha.-position, and wherein R.sup.2 may optionally be further
substituted. Typically, R.sup.2 is an aryl or a heteroaryl group,
wherein the aryl or the heteroaryl group is substituted at the
.alpha. and .alpha.' positions, and wherein R.sup.2 may optionally
be further substituted. Typically, R.sup.2 is a phenyl or a 5- or
6-membered heteroaryl group, wherein the phenyl or the heteroaryl
group is substituted at the .alpha. and .alpha.' positions, and
wherein R.sup.2 may optionally be further substituted. For example,
R.sup.2 may be a phenyl group substituted at the 2- and 6-positions
or a phenyl group substituted at the 2-, 4- and 6-positions.
[0101] In one embodiment, the parent phenyl or 5- or 6-membered
heteroaryl group of R.sup.2 may be selected from phenyl, pyridinyl
(such as pyridin-3-yl or pyridin-4-yl), pyridazinyl, pyrimidinyl
(such as pyrimidin-2-yl or pyrimidin-5-yl), pyrazinyl, pyrrolyl,
furanyl, thiophenyl, pyrazolyl (such as pyrazol-1-yl, pyrazol-3-yl
or pyrazol-4-yl), imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, triazolyl or oxadiazolyl. Typically, the parent
phenyl or 5- or 6-membered heteroaryl group of R.sup.2 may be
selected from phenyl, pyridinyl (such as pyridin-3-yl or
pyridin-4-yl), pyridazinyl, pyrimidinyl (such as pyrimidin-2-yl or
pyrimidin-5-yl), pyrrolyl, pyrazolyl (such as pyrazol-1-yl,
pyrazol-3-yl or pyrazol-4-yl), imidazolyl or triazolyl. Typically,
the parent phenyl or 5- or 6-membered heteroaryl group of R.sup.2
may be selected from phenyl, pyridinyl (such as pyridin-3-yl or
pyridin-4-yl), pyridazinyl or pyrimidinyl (such as pyrimidin-2-yl
or pyrimidin-5-yl).
[0102] In another embodiment, R.sup.2 is a cyclic group substituted
at the .alpha. and .alpha.' positions, wherein R.sup.2 may
optionally be further substituted. For example, R.sup.2 may be a
cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group
substituted at the .alpha. and .alpha.' positions.
[0103] In any of the above embodiments, typical substituents at the
.alpha. and/or .alpha.' positions of the parent cyclic group of
R.sup.2 comprise a carbon atom. For example, typical substituents
at the .alpha. and/or .alpha.' positions of the parent cyclic group
of R.sup.2 may be independently selected from --R.sup..gamma.,
--OR.sup..gamma. or --CORY groups, wherein each R.sup..gamma. is
independently selected from a C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6
cyclic group and wherein each R.sup..gamma. is optionally further
substituted with one or more halo groups. More typically, the
substituents at the .alpha. and/or .alpha.' positions are
independently selected from alkyl or cycloalkyl groups, such as
C.sub.3-C.sub.6 branched alkyl and C.sub.3-C.sub.6 cycloalkyl
groups, e.g. isopropyl, cyclopropyl, cyclohexyl or t-butyl groups,
wherein the alkyl and cycloalkyl groups are optionally further
substituted with one or more fluoro and/or chloro groups.
[0104] In one aspect of any of the above embodiments, each
substituent at the .alpha. and .alpha.' positions comprises a
carbon atom.
[0105] Other typical substituents at the .alpha. and/or .alpha.'
positions of the parent cyclic group of R.sup.2 may include
cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or
heteroaryl rings which are fused to the parent cyclic group across
the .alpha.,.beta. and/or .alpha.',.beta.' positions respectively.
Such fused cyclic groups are described in greater detail below.
[0106] In one embodiment, R.sup.2 is a fused aryl or a fused
heteroaryl group, wherein the aryl or heteroaryl group is fused to
one or more cycloalkyl, cycloalkenyl, non-aromatic heterocyclic,
aryl or heteroaryl rings, wherein R.sup.2 may optionally be further
substituted. Typically, a cycloalkyl, cycloalkenyl, non-aromatic
heterocyclic, aryl or heteroaryl ring is fused to the aryl or
heteroaryl group across the .alpha.,.beta. positions. Typically,
the aryl or heteroaryl group is also substituted at the .alpha.'
position, for example with a substituent selected from --R.sup.9,
--OR.sup.9 and --COR.sup.9, wherein each R.sup.9 is independently
selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein
each R9 is optionally further substituted with one or more halo
groups. Typically in such an embodiment, R.sup.2 is bicyclic or
tricyclic.
[0107] More typically, R.sup.2 is a fused phenyl or a fused 5- or
6-membered heteroaryl group, wherein the phenyl or the 5- or
6-membered heteroaryl group is fused to one or more cycloalkyl,
cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl rings,
wherein R.sup.2 may optionally be further substituted. Typically, a
cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or
heteroaryl ring is fused to the phenyl or the 5- or 6-membered
heteroaryl group across the .alpha.,.beta. positions so as to form
a 4- to 6-membered fused ring structure. Typically, the phenyl or
the 5- or 6-membered heteroaryl group is also substituted at the
.alpha.' position, for example with a substituent selected from
--R.sup.9, --OR.sup.9 and --COR.sup.9, wherein each R.sup.9 is
independently selected from a C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6
cyclic group and wherein each R.sup.9 is optionally further
substituted with one or more halo groups. Typically in such an
embodiment, R.sup.2 is bicyclic or tricyclic.
[0108] In another embodiment, R.sup.2 is a fused aryl or a fused
heteroaryl group, wherein the aryl or heteroaryl group is fused to
two or more independently selected cycloalkyl, cycloalkenyl,
non-aromatic heterocyclic, aryl or heteroaryl rings, wherein
R.sup.2 may optionally be further substituted. Typically, the two
or more cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl
or heteroaryl rings are each ortho-fused to the aryl or heteroaryl
group, i.e. each fused cycloalkyl, cycloalkenyl, non-aromatic
heterocyclic, aryl or heteroaryl ring has only two atoms and one
bond in common with the aryl or heteroaryl group. Typically,
R.sup.2 is tricyclic.
[0109] In yet another embodiment, R.sup.2 is a fused aryl or a
fused heteroaryl group, wherein a first cycloalkyl, cycloalkenyl,
non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the
aryl or heteroaryl group across the .alpha.,.beta. positions and a
second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or
heteroaryl ring is fused to the aryl or heteroaryl group across the
.alpha.',.beta.' positions, wherein R.sup.2 may optionally be
further substituted. Typically in such an embodiment, R.sup.2 is
tricyclic.
[0110] More typically, R.sup.2 is a fused phenyl or a fused 5- or
6-membered heteroaryl group, wherein a first cycloalkyl,
cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is
fused to the phenyl or the 5- or 6-membered heteroaryl group across
the .alpha.,.beta. positions so as to form a first 4- to 6-membered
fused ring structure, and a second cycloalkyl, cycloalkenyl,
non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the
phenyl or the 5- or 6-membered heteroaryl group across the
.alpha.',.beta.' positions so as to form a second 4- to 6-membered
fused ring structure, wherein R.sup.2 may optionally be further
substituted. Typically in such an embodiment, R.sup.2 is
tricyclic.
[0111] In one embodiment, --R.sup.2 has a formula selected
from:
##STR00014##
[0112] wherein: [0113] A.sup.1 and A.sup.2 are each independently
selected from an optionally substituted alkylene or alkenylene
group, wherein one or more carbon atoms in the backbone of the
alkylene or alkenylene group may optionally be replaced by one or
more heteroatoms N, O or S; [0114] each R.sup.a is independently
selected from --R.sup.aa, --OR.sup.aa or --COR.sup.aa; [0115] each
R.sup.b is independently selected from hydrogen, halo, --NO.sub.2,
--CN, --R.sup.aa, --OR.sup.aa or --COR.sup.aa; [0116] provided that
any R.sup.a or R.sup.b that is directly attached to a ring nitrogen
atom is not halo, --NO.sub.2, --CN or --OR.sup.aa; [0117] each
R.sup.c is independently selected from hydrogen, halo, --OH,
--NO.sub.2, --CN, --R--, --OR.sup.cc, --COR--, --COOR--,
--CONH.sub.2, --CONHR.sup.cc or --CON(R.sup.cc).sub.2; [0118] each
R.sup.aa is independently selected from a C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or a 3- to
7-membered cyclic group, wherein each R.sup.aa is optionally
substituted; and [0119] each R.sup.cc is independently selected
from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or a 3- to 7-membered cyclic group, or any
two R.sup.cc attached to the same nitrogen atom may, together with
the nitrogen atom to which they are attached, form a 3- to
7-membered heterocyclic group, wherein each R.sup.cc is optionally
substituted.
[0120] Typically, any ring containing A.sup.1 or A.sup.2 is a 5- or
6-membered ring. Typically, A.sup.1 and A.sup.2 are each
independently selected from an optionally substituted
straight-chained alkylene group or an optionally substituted
straight-chained alkenylene group, wherein one or two carbon atoms
in the backbone of the alkylene or alkenylene group may optionally
be replaced by one or two heteroatoms independently selected from
nitrogen and oxygen. More typically, A.sup.1 and A.sup.2 are each
independently selected from an optionally substituted
straight-chained alkylene group, wherein one carbon atom in the
backbone of the alkylene group may optionally be replaced by an
oxygen atom. Typically, no heteroatom in A.sup.1 or A.sup.2 is
directly attached to another ring heteroatom. Typically, A.sup.1
and A.sup.2 are unsubstituted or substituted with one or more
substituents independently selected from halo, --OH, --CN,
--NO.sub.2, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
--O(C.sub.1-C.sub.4 alkyl) or --O(C.sub.1-C.sub.4 haloalkyl). More
typically, A.sup.1 and A.sup.2 are unsubstituted or substituted
with one or more fluoro and/or chloro groups. Where R.sup.2
contains both A.sup.1 and A.sup.2 groups, A.sup.1 and A.sup.2 may
be the same or different. Typically, A.sup.1 and A.sup.2 are the
same.
[0121] Where R.sup.aa is a substituted C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl group, typically
the C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl or
C.sub.2-C.sub.6 alkynyl group is substituted with one or more (e.g.
one or two) substituents independently selected from halo, --OH,
--CN, --NO.sub.2, --O(C.sub.1-C.sub.4 alkyl) or --O(C.sub.1-C.sub.4
haloalkyl).
[0122] Where R.sup.aa is a substituted 3- to 7-membered cyclic
group, typically the 3- to 7-membered cyclic group is substituted
with one or more (e.g. one or two) substituents independently
selected from halo, --OH, --NH.sub.2, --CN, --NO.sub.2, --B.sup.1,
--OB.sup.1, --NHB.sup.1, --N(B.sup.1).sub.2, --CONH.sub.2,
--CONHB.sup.1, --CON(B.sup.1).sub.2, --NHCOB.sup.1,
--NB.sup.1COB.sup.1, or --B.sup.11--; [0123] wherein each B.sup.1
is independently selected from a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.3-C.sub.6
cycloalkyl or phenyl group, or a 4- to 6-membered heterocyclic
group containing one or two ring heteroatoms N and/or O, or two
B.sup.1 together with the nitrogen atom to which they are attached
may form a 4- to 6-membered heterocyclic group containing one or
two ring heteroatoms N and/or O, wherein any B.sup.1 may optionally
be halo-substituted and/or substituted with one or two substituents
independently selected from --OH, --NH.sub.2, --OB.sup.12,
--NHB.sup.12 or --N(B.sup.12).sub.2; [0124] wherein each B.sup.11
is independently selected from a C.sub.1-C.sub.5 alkylene or
C.sub.2-C.sub.5 alkenylene group, wherein one or two carbon atoms
in the backbone of the alkylene or alkenylene group may optionally
be replaced by one or two heteroatoms N and/or O, and wherein the
alkylene or alkenylene group may optionally be halo-substituted
and/or substituted with one or two substituents independently
selected from --OH, --NH.sub.2, --OB.sup.12, --NHB.sup.12 or
--N(B.sup.12).sub.2; and [0125] wherein each B.sup.12 is
independently selected from a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group. Typically, any divalent group
--B.sup.11-- forms a 4- to 6-membered fused ring.
[0126] Typically, each R.sup.a is --R.sup.aa. More typically, each
R.sup.a is independently selected from a C.sub.1-C.sub.6 alkyl (in
particular C.sub.3-C.sub.6 branched alkyl) or C.sub.3-C.sub.6
cycloalkyl group, wherein each R.sup.a is optionally further
substituted with one or more halo groups. More typically, each
R.sup.a is independently selected from a C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.4 cycloalkyl or
C.sub.3-C.sub.4 halocycloalkyl group. Where a group R.sup.a is
present at both the .alpha.- and .alpha.'-positions, each R.sup.a
may be the same or different. Typically, each R.sup.a is the
same.
[0127] Typically, each R.sup.b is independently selected from
hydrogen or halo. More typically, each R.sup.b is hydrogen.
[0128] Typically, each R.sup.c is independently selected from
hydrogen, halo, --OH, --NO.sub.2, --CN, --R or --OR.sup.cc. More
typically, each R.sup.c is independently selected from hydrogen,
halo, --CN, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl,
cyclopropyl or halocyclopropyl. Most typically, each R.sup.c is
independently selected from hydrogen or halo.
[0129] Typically, each R.sup.cc is independently selected from a
C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.6 cycloalkyl group, or any
two R.sup.cc attached to the same nitrogen atom may, together with
the nitrogen atom to which they are attached, form a 3- to
6-membered saturated heterocyclic group, wherein each R is
optionally substituted. Where R.sup.cc is substituted, typically
Rce is substituted with one or more halo, --OH, --CN, --NO.sub.2,
--O(C.sub.1-C.sub.4 alkyl) or --O(C.sub.1-C.sub.4 haloalkyl)
groups. More typically, each R.sup.cc is independently selected
from a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.3-C.sub.4 cycloalkyl or C.sub.3-C.sub.4 halocycloalkyl
group.
[0130] In one embodiment, --R.sup.2 has a formula selected
from:
##STR00015##
[0131] wherein R.sup.5 and R.sup.6 are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.4
cycloalkyl and C.sub.3-C.sub.4 halocycloalkyl, and R.sup.d is
hydrogen, halo, --OH, --NO.sub.2, --CN, --R.sup.dd, --OR.sup.dd,
--COR.sup.dd, --COOR.sup.dd, --CONH.sub.2, --CONHR.sup.dd or
--CON(R.sup.dd).sub.2, wherein each --R.sup.dd is independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.3-C.sub.4 cycloalkyl and C.sub.3-C.sub.4 halocycloalkyl.
Typically, R.sup.5 and R.sup.6 are independently selected from
C.sub.1-C.sub.4 alkyl, and R.sup.d is hydrogen, halo, --CN,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, cyclopropyl or
halocyclopropyl. More typically, R.sup.5 and R.sup.6 are
independently selected from C.sub.1-C.sub.4 alkyl, and R.sup.d is
hydrogen or halo.
[0132] Typically, --R.sup.2 has a formula selected from:
##STR00016##
[0133] In one embodiment, --R.sup.2 has a formula selected
from:
##STR00017##
[0134] wherein A.sup.1 and A.sup.2 are each independently selected
from an optionally substituted alkylene or alkenylene group,
wherein one or more carbon atoms in the backbone of the alkylene or
alkenylene group may optionally be replaced by one or more
heteroatoms N, O or S, and wherein R.sup.e is hydrogen or any
optional substituent. R.sup.e and any optional substituent attached
to A.sup.1 or A.sup.2 may together with the atoms to which they are
attached form a further fused cycloalkyl, cycloalkenyl,
non-aromatic heterocyclic, aryl or heteroaryl ring which may itself
be optionally substituted. Similarly, any optional substituent
attached to A.sup.1 and any optional substituent attached to
A.sup.2 may also together with the atoms to which they are attached
form a further fused cycloalkyl, cycloalkenyl, non-aromatic
heterocyclic, aryl or heteroaryl ring which may itself be
optionally substituted.
[0135] In one embodiment, R.sup.e is hydrogen, halo, --OH,
--NO.sub.2, --CN, --R.sup.ee, --OR.sup.ee, --COR.sup.ee,
--COOR.sup.ee, --CONH.sub.2, --CONHR.sup.ee or
--CON(R.sup.ee).sub.2, wherein each --R.sup.ee is independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.3-C.sub.4 cycloalkyl and C.sub.3-C.sub.4 halocycloalkyl.
Typically, R.sup.e is hydrogen or a halo, hydroxyl, --CN,
--NO.sub.2, --R.sup.ee or --OR.sup.ee group, wherein R.sup.ee is a
C.sub.1-C.sub.4 alkyl group which may optionally be
halo-substituted. More typically, R.sup.e is hydrogen or halo.
[0136] Typically, any ring containing A.sup.1 or A.sup.2 is a 5- or
6-membered ring. Typically, A.sup.1 and A.sup.2 are each
independently selected from an optionally substituted
straight-chained alkylene group or an optionally substituted
straight-chained alkenylene group, wherein one or two carbon atoms
in the backbone of the alkylene or alkenylene group may optionally
be replaced by one or two heteroatoms independently selected from
nitrogen and oxygen. More typically, A.sup.1 and A.sup.2 are each
independently selected from an optionally substituted
straight-chained alkylene group, wherein one carbon atom in the
backbone of the alkylene group may optionally be replaced by an
oxygen atom. Typically, no heteroatom in A.sup.1 or A.sup.2 is
directly attached to another ring heteroatom. Typically, A.sup.1
and A.sup.2 are unsubstituted or substituted with one or more halo,
hydroxyl, --CN, --NO.sub.2, --B.sup.3 or --OB.sup.3 groups, wherein
B.sup.3 is a C.sub.1-C.sub.4 alkyl group which may optionally be
halo-substituted. More typically, A.sup.1 and A.sup.2 are
unsubstituted or substituted with one or more fluoro and/or chloro
groups. Where R.sup.2 contains both A.sup.1 and A.sup.2 groups,
A.sup.1 and A.sup.2 may be the same or different. Typically,
A.sup.1 and A.sup.2 are the same.
[0137] In a further embodiment, --R.sup.2 has a formula selected
from:
##STR00018## ##STR00019##
[0138] wherein R.sup.6 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.3-C.sub.4 cycloalkyl or C.sub.3-C.sub.4
halocycloalkyl, and R.sup.f is hydrogen, halo, --OH, --NO.sub.2,
--CN, --R.sup.ff, --OR.sup.ff, --COR.sup.ff, --COOR.sup.ff,
--CONH.sub.2, --CONHR.sup.ff or --CON(R.sup.ff).sub.2, wherein each
--R.sup.ff is independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.4 cycloalkyl and
C.sub.3-C.sub.4 halocycloalkyl. Typically, R.sup.6 is
C.sub.1-C.sub.4 alkyl, and R.sup.f is hydrogen, halo, --CN,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, cyclopropyl or
halocyclopropyl. Typically, R.sup.6 is C.sub.1-C.sub.4 alkyl, and
R.sup.f is hydrogen or halo.
[0139] Typically, --R.sup.2 has the formula:
##STR00020##
[0140] More typically, --R.sup.2 has the formula:
##STR00021##
[0141] Yet other typical substituents at the .alpha.-position of
the parent cyclic group of R.sup.2 may include monovalent
heterocyclic groups and monovalent aromatic groups, wherein a ring
atom of the heterocyclic or aromatic group is directly attached via
a single bond to the .alpha.-ring atom of the parent cyclic group,
wherein the heterocyclic or aromatic group may optionally be
substituted, and wherein the parent cyclic group may optionally be
further substituted. Such R.sup.2 groups are described in greater
detail below.
[0142] In one embodiment, the .alpha.-substituted parent cyclic
group of R.sup.2 is a 5- or 6-membered cyclic group, wherein the
cyclic group may optionally be further substituted. In one
embodiment, the .alpha.-substituted parent cyclic group of R.sup.2
is an aryl or a heteroaryl group, all of which may optionally be
further substituted. In one embodiment, the .alpha.-substituted
parent cyclic group of R.sup.2 is a phenyl or a 5- or 6-membered
heteroaryl group, all of which may optionally be further
substituted. In one embodiment, the .alpha.-substituted parent
cyclic group of R.sup.2 is a phenyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl group,
all of which may optionally be further substituted. In one
embodiment, the .alpha.-substituted parent cyclic group of R.sup.2
is a phenyl or pyrazolyl group, both of which may optionally be
further substituted. In one embodiment, the .alpha.-substituted
parent cyclic group of R.sup.2 is a phenyl group, which may
optionally be further substituted.
[0143] In one embodiment, the .alpha.-substituted parent cyclic
group of R.sup.2 is substituted at the .alpha. and .alpha.'
positions, and may optionally be further substituted. For example,
the .alpha.-substituted parent cyclic group of R.sup.2 may be a
phenyl group substituted at the 2- and 6-positions, or a phenyl
group substituted at the 2-, 4- and 6-positions.
[0144] In one embodiment, R.sup.2 is a parent cyclic group
substituted at the .alpha.-position with a monovalent heterocyclic
group or a monovalent aromatic group, wherein the heterocyclic or
aromatic group may optionally be substituted, and wherein the
parent cyclic group may optionally be further substituted. In one
embodiment, the monovalent heterocyclic or aromatic group at the
.alpha.-position is a phenyl or a 5- or 6-membered heterocyclic
group, all of which may optionally be substituted. In one
embodiment, the monovalent heterocyclic or aromatic group at the
.alpha.-position is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,
oxadiazolyl, azetinyl, azetidinyl, oxetanyl, thietanyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,
pyrazolidinyl, imidazolidinyl, 1,3-dioxolanyl, 1,2-oxathiolanyl,
1,3-oxathiolanyl, piperidinyl, tetrahydropyranyl, piperazinyl,
1,4-dioxanyl, thianyl, morpholinyl, thiomorpholinyl or
1-methyl-2-oxo-1,2-dihydropyridinyl group, all of which may
optionally be substituted. In one embodiment, the monovalent
heterocyclic or aromatic group at the .alpha.-position is a phenyl,
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl,
thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, azetinyl, azetidinyl, oxetanyl, thietanyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,
pyrazolidinyl, imidazolidinyl, 1,3-dioxolanyl, 1,2-oxathiolanyl,
1,3-oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl,
piperazinyl, 1,4-dioxanyl, morpholinyl or thiomorpholinyl group,
all of which may optionally be substituted. In one embodiment, the
monovalent heterocyclic or aromatic group at the .alpha.-position
is a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,
pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, piperidinyl or
tetrahydropyranyl group, all of which may optionally be
substituted. In one embodiment, the monovalent heterocyclic or
aromatic group at the .alpha.-position is a phenyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl,
thiazolyl, tetrahydropyranyl or 1-methyl-2-oxo-1,2-dihydropyridinyl
group, all of which may optionally be substituted. In one
embodiment, the monovalent heterocyclic or aromatic group at the
.alpha.-position is a phenyl, pyridinyl, pyrimidinyl, pyrazolyl,
imidazolyl, isoxazolyl, thiazolyl or tetrahydropyranyl group, all
of which may optionally be substituted. In one embodiment, the
monovalent heterocyclic or aromatic group at the .alpha.-position
is a phenyl, pyridinyl, pyrimidinyl or pyrazolyl group, all of
which may optionally be substituted. In one embodiment, the
monovalent heterocyclic or aromatic group at the .alpha.-position
is an unsubstituted phenyl, pyridinyl, pyrimidinyl or pyrazolyl
group. In one embodiment, the monovalent heterocyclic group at the
.alpha.-position is a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl
group, all of which may optionally be substituted. In one
embodiment, the monovalent heterocyclic group at the
.alpha.-position is an unsubstituted pyridin-3-yl group or an
optionally substituted pyridin-4-yl group.
[0145] For any of these monovalent heterocyclic or aromatic groups
at the .alpha.-position mentioned in the immediately preceding
paragraph, the monovalent heterocyclic or aromatic group may
optionally be substituted with one or two substituents
independently selected from halo, --OH, --NH.sub.2, --CN,
--NO.sub.2, --B.sup.4, --OB.sup.4, --NHB.sup.4, --N(B.sup.4).sub.2,
--CONH.sub.2, --CONHB.sup.4, --CON(B.sup.4).sub.2, --NHCOB.sup.4,
--NB.sup.4COB.sup.4, or --B.sup.44--; [0146] wherein each B.sup.4
is independently selected from a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.3-C.sub.6
cycloalkyl or phenyl group, or a 4- to 6-membered heterocyclic
group containing one or two ring heteroatoms N and/or O, or two
B.sup.4 together with the nitrogen atom to which they are attached
may form a 4- to 6-membered heterocyclic group containing one or
two ring heteroatoms N and/or O, wherein any B.sup.4 may optionally
be halo-substituted and/or substituted with one or two substituents
independently selected from --OH, --NH.sub.2, --OB.sup.45,
--NHB.sup.45 or --N(B.sup.45).sub.2; [0147] wherein each B.sup.44
is independently selected from a C.sub.1-C.sub.8 alkylene or
C.sub.2-C.sub.8 alkenylene group, wherein one or two carbon atoms
in the backbone of the alkylene or alkenylene group may optionally
be replaced by one or two heteroatoms N and/or O, and wherein the
alkylene or alkenylene group may optionally be halo-substituted
and/or substituted with one or two substituents independently
selected from --OH, --NH.sub.2, --OB.sup.45, --NHB.sup.45 or
--N(B.sup.45).sub.2; and [0148] wherein each B.sup.45 is
independently selected from a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group.
[0149] Typically, any divalent group --B.sup.44-- forms a 4- to
6-membered fused ring.
[0150] In one embodiment, the monovalent heterocyclic or aromatic
group at the .alpha.-position is a phenyl, pyridinyl, pyrimidinyl
or pyrazolyl group, all of which may optionally be substituted with
one or two substituents independently selected from halo, --OH,
--NH.sub.2, --CN, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl, --OB.sup.4 or
--N(B.sup.4).sub.2, wherein B.sup.4 is independently selected from
C.sub.1-C.sub.4 alkyl which may optionally be halo-substituted. In
one embodiment, the monovalent heterocyclic group at the
.alpha.-position is a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl
group, all of which may optionally be substituted with one or two
substituents independently selected from halo, --OH, --NH.sub.2,
--CN, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl, --OB.sup.4 or
--N(B.sup.4).sub.2, wherein B.sup.4 is independently selected from
C.sub.1-C.sub.4 alkyl which may optionally be halo-substituted. In
one embodiment, the monovalent heterocyclic group at the
.alpha.-position is an unsubstituted pyridin-3-yl group or a
pyridin-4-yl group optionally substituted with one or two
substituents independently selected from halo, --OH, --NH.sub.2,
--CN, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl, --OB.sup.4 or
--N(B.sup.4).sub.2, wherein B.sup.4 is independently selected from
C.sub.1-C.sub.4 alkyl which may optionally be halo-substituted.
Alternatively, any of these monovalent phenyl or heterocyclic
groups at the .alpha.-position may optionally be substituted with
one or two substituents independently selected from halo, --OH,
--NH.sub.2, --CN, --NO.sub.2, --B.sup.4, --OB.sup.4, --NHB.sup.4 or
--N(B.sup.4).sub.2, wherein each B.sup.4 is independently selected
from a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl or
C.sub.2-C.sub.4 alkynyl group all of which may optionally be
halo-substituted.
[0151] In one embodiment, R.sup.2 is a parent cyclic group
substituted at the .alpha.-position with a monovalent heterocyclic
group or a monovalent aromatic group, wherein the heterocyclic or
aromatic group may optionally be substituted, and wherein the
parent cyclic group may optionally be further substituted. In one
embodiment, such further substituents are in the .alpha.' position
of the .alpha.-substituted parent cyclic group of R.sup.2. Such
further substituents may be independently selected from halo,
--R.sup..epsilon., --OR.sup..epsilon. or --COR.sup..epsilon.
groups, wherein each R.sup..epsilon. is independently selected from
a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl or C.sub.2-C.sub.6 cyclic group and wherein each
R.sup..epsilon. is optionally further substituted with one or more
halo groups. Typically, such further substituents on the
.alpha.-substituted parent cyclic group of R.sup.2 are
independently selected from halo, C.sub.1-C.sub.6 alkyl (in
particular C.sub.3-C.sub.6 branched alkyl) or C.sub.3-C.sub.6
cycloalkyl groups, e.g. fluoro, chloro, isopropyl, cyclopropyl,
cyclohexyl or t-butyl groups, wherein the alkyl and cycloalkyl
groups are optionally further substituted with one or more fluoro
and/or chloro groups.
[0152] In one embodiment, --R.sup.2 has a formula selected
from:
##STR00022##
[0153] wherein R.sup.7 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.3-C.sub.6 cycloalkyl or C.sub.3-C.sub.6
halocycloalkyl, R.sup.8 is a 5- or 6-membered, optionally
substituted heterocyclic or aromatic group, and R.sup.g is
hydrogen, halo, --OH, --NO.sub.2, --CN, --R.sup.gg, --OR.sup.gg,
--COR.sup.gg, --COOR.sup.gg, --CONH.sub.2, --CONHR.sup.gg or
--CON(R.sup.gg).sub.2, wherein each --R.sup.gg is independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.3-C.sub.4 cycloalkyl and C.sub.3-C.sub.4 halocycloalkyl. In
one embodiment, the optional substituents on the heterocyclic or
aromatic group are independently selected from halo, --OH,
--NH.sub.2, --CN, --NO.sub.2, --B.sup.5, --OB.sup.5, --NHB.sup.5,
--N(B.sup.5).sub.2, --CONH.sub.2, --CONHB.sup.5,
--CON(B.sup.5).sub.2, --NHCOB.sup.5, --NB.sup.5COB.sup.5, or
--B.sup.55--; [0154] wherein each B.sup.5 is independently selected
from a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.3-C.sub.6 cycloalkyl or phenyl
group, or a 4- to 6-membered heterocyclic group containing one or
two ring heteroatoms N and/or O, or two B.sup.5 together with the
nitrogen atom to which they are attached may form a 4- to
6-membered heterocyclic group containing one or two ring
heteroatoms N and/or O, wherein any B.sup.5 may optionally be
halo-substituted and/or substituted with one or two substituents
independently selected from --OH, --NH.sub.2, --OB.sup.56,
--NHB.sup.56 or --N(B.sup.56).sub.2; [0155] wherein each B.sub.55
is independently selected from a C.sub.1-C.sub.8 alkylene or
C.sub.2-C.sub.8 alkenylene group, wherein one or two carbon atoms
in the backbone of the alkylene or alkenylene group may optionally
be replaced by one or two heteroatoms N and/or O, and wherein the
alkylene or alkenylene group may optionally be halo-substituted
and/or substituted with one or two substituents independently
selected from --OH, --NH.sub.2, --OB.sup.56, --NHB.sup.56 or
--N(B.sup.56).sub.2; and [0156] wherein each B.sup.56 is
independently selected from a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group.
[0157] Typically, any divalent group --B.sup.55-- forms a 4- to
6-membered fused ring. Typically, R.sup.7 is C.sub.1-C.sub.4 alkyl,
R.sup.8 is a 5- or 6-membered, optionally substituted heterocyclic
or aromatic group, and R.sup.g is hydrogen, halo, --CN,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, cyclopropyl or
halocyclopropyl. More typically, R.sup.7 is C.sub.1-C.sub.4 alkyl,
R.sup.8 is a 5- or 6-membered, optionally substituted heterocyclic
or aromatic group, and R.sup.g is hydrogen or halo. In one
embodiment, the optional substituents on the heterocyclic or
aromatic group are independently selected from halo, --OH,
--NH.sub.2, --CN, --NO.sub.2, --B.sup.5, --OB.sup.5, --NHB.sup.5 or
--N(B.sup.5).sub.2, wherein each B.sup.5 is independently selected
from a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl or
C.sub.2-C.sub.4 alkynyl group all of which may optionally be
halo-substituted. Typically, the optional substituents on the
heterocyclic or aromatic group are independently selected from
halo, --OH, --NH.sub.2, --CN, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
haloalkyl, --OB.sup.5 or --N(B.sup.5).sub.2, wherein B.sup.5 is
independently selected from C.sub.1-C.sub.4 alkyl which may
optionally be halo-substituted.
[0158] Typically, --R.sup.2 has a formula selected from:
##STR00023##
[0159] wherein R.sup.8 is a 5- or 6-membered, optionally
substituted heterocyclic or aromatic group. In one embodiment, the
optional substituents on the heterocyclic or aromatic group are
independently selected from halo, --OH, --NH.sub.2, --CN,
--NO.sub.2, --B.sup.6, --OB.sup.6, --NHB.sup.6, --N(B.sup.6).sub.2,
--CONH.sub.2, --CONHB.sup.6, --CON(B.sup.6).sub.2, --NHCOB.sup.6,
--NB.sup.6COB.sup.6, or --B.sup.66--; [0160] wherein each B.sup.6
is independently selected from a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.3-C.sub.6
cycloalkyl or phenyl group, or a 4- to 6-membered heterocyclic
group containing one or two ring heteroatoms N and/or O, or two
B.sup.6 together with the nitrogen atom to which they are attached
may form a 4- to 6-membered heterocyclic group containing one or
two ring heteroatoms N and/or O, wherein any B.sup.6 may optionally
be halo-substituted and/or substituted with one or two substituents
independently selected from --OH, --NH.sub.2, --OB.sup.67,
--NHB.sup.67 or --N(B.sup.67).sub.2; [0161] wherein each B.sup.66
is independently selected from a C.sub.1-C.sub.8 alkylene or
C.sub.2-C.sub.8 alkenylene group, wherein one or two carbon atoms
in the backbone of the alkylene or alkenylene group may optionally
be replaced by one or two heteroatoms N and/or O, and wherein the
alkylene or alkenylene group may optionally be halo-substituted
and/or substituted with one or two substituents independently
selected from --OH, --NH.sub.2, --OB.sup.67, --NHB.sup.67 or
--N(B.sup.67).sub.2; and [0162] wherein each B.sup.67 is
independently selected from a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group.
[0163] Typically, any divalent group --B.sup.66-- forms a 4- to
6-membered fused ring. Typically, the optional substituents on the
heterocyclic or aromatic group are independently selected from
halo, --OH, --NH.sub.2, --CN, --NO.sub.2, --B.sup.6, --OB.sup.6,
--NHB.sup.6 or --N(B.sup.6).sub.2, wherein each B.sup.6 is
independently selected from a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4 alkynyl group all of
which may optionally be halo-substituted. Typically, the optional
substituents on the heterocyclic or aromatic group are
independently selected from halo, --OH, --NH.sub.2, --CN,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4
alkynyl, C.sub.1-C.sub.4 haloalkyl, --OB.sup.6 or
--N(B.sup.6).sub.2, wherein B.sup.6 is independently selected from
C.sub.1-C.sub.4 alkyl which may optionally be halo-substituted.
[0164] In one embodiment, R.sup.2 is a parent cyclic group
substituted at the .alpha.-position with a monovalent heterocyclic
group or a monovalent aromatic group, wherein the heterocyclic or
aromatic group may optionally be substituted, and wherein the
parent cyclic group may optionally be further substituted. The
further substituents on the .alpha.-substituted parent cyclic group
of R.sup.2 also include cycloalkyl, cycloalkenyl, non-aromatic
heterocyclic, aryl or heteroaryl rings which are fused to the
.alpha.-substituted parent cyclic group of R.sup.2. Typically, the
cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or
heteroaryl rings are ortho-fused to the .alpha.-substituted parent
cyclic group of R.sup.2, i.e. each fused cycloalkyl, cycloalkenyl,
non-aromatic heterocyclic, aryl or heteroaryl ring has only two
atoms and one bond in common with the .alpha.-substituted parent
cyclic group of R.sup.2. Typically, the cycloalkyl, cycloalkenyl,
non-aromatic heterocyclic, aryl or heteroaryl rings are ortho-fused
to the .alpha.-substituted parent cyclic group of R.sup.2 across
the .alpha.',.beta.' positions.
[0165] In one embodiment, --R.sup.2 has a formula selected
from:
##STR00024##
[0166] wherein R.sup.8 is a 5- or 6-membered, optionally
substituted heterocyclic or aromatic group, and R.sup.h is
hydrogen, halo, --OH, --NO.sub.2, --CN, --R.sup.hh, --OR.sup.hh,
--COR.sup.hh, --COOR.sup.hh, --CONH.sub.2, --CONHR.sup.hh or
--CON(R.sup.hh).sub.2, wherein each --R.sup.hh is independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.3-C.sub.4 cycloalkyl and C.sub.3-C.sub.4 halocycloalkyl. In
one embodiment, the optional substituents on the heterocyclic or
aromatic group are independently selected from halo, --OH,
--NH.sub.2, --CN, --NO.sub.2, --B.sup.7, --OB.sup.7, --NHB.sup.7,
--N(B.sup.7).sub.2, --CONH.sub.2, --CONHB.sup.7,
--CON(B.sup.7).sub.2, --NHCOB.sup.7, --NB.sup.7COB.sup.7, or
--B.sup.77--; [0167] wherein each B.sup.7 is independently selected
from a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.3-C.sub.6 cycloalkyl or phenyl
group, or a 4- to 6-membered heterocyclic group containing one or
two ring heteroatoms N and/or O, or two B.sup.7 together with the
nitrogen atom to which they are attached may form a 4- to
6-membered heterocyclic group containing one or two ring
heteroatoms N and/or O, wherein any B.sup.7 may optionally be
halo-substituted and/or substituted with one or two substituents
independently selected from --OH, --NH.sub.2, --OB.sup.78,
--NHB.sup.78 or --N(B.sup.78).sub.2; [0168] wherein each B.sup.77
is independently selected from a C.sub.1-C.sub.8 alkylene or
C.sub.2-C.sub.8 alkenylene group, wherein one or two carbon atoms
in the backbone of the alkylene or alkenylene group may optionally
be replaced by one or two heteroatoms N and/or O, and wherein the
alkylene or alkenylene group may optionally be halo-substituted
and/or substituted with one or two substituents independently
selected from --OH, --NH.sub.2, --OB.sup.78, --NHB.sup.78 or
--N(B.sup.78).sub.2; and [0169] wherein each B.sup.78 is
independently selected from a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group.
[0170] Typically, any divalent group --B.sup.77-- forms a 4- to
6-membered fused ring. Typically, R.sup.h is hydrogen, halo, --CN,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, cyclopropyl or
halocyclopropyl. More typically, R.sup.h is hydrogen or halo.
Typically, the optional substituents on the heterocyclic or
aromatic group are independently selected from halo, --OH,
--NH.sub.2, --CN, --NO.sub.2, --B.sup.7, --OB.sup.7, --NHB.sup.7 or
--N(B.sup.7).sub.2, wherein each B.sup.7 is independently selected
from a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl or
C.sub.2-C.sub.4 alkynyl group all of which may optionally be
halo-substituted. Typically, the optional substituents on the
heterocyclic or aromatic group are selected from halo, --OH,
--NH.sub.2, --CN, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl, --OB.sup.7 or
--N(B.sup.7).sub.2, wherein B.sup.7 is independently selected from
C.sub.1-C.sub.4 alkyl which may optionally be halo-substituted.
[0171] In one embodiment, --R.sup.2 has a formula selected
from:
##STR00025##
[0172] wherein R.sup.8 is a 5- or 6-membered, optionally
substituted heterocyclic or aromatic group. In one embodiment, the
optional substituents on the heterocyclic or aromatic group are
independently selected from halo, --OH, --NH.sub.2, --CN,
--NO.sub.2, --B.sup.8, --OB.sup.8, --NHB.sup.8, --N(B.sup.8).sub.2,
--CONH.sub.2, --CONHB.sup.8, --CON(B.sup.8).sub.2, --NHCOB.sup.8,
--NB.sup.8COB.sup.8, or --B.sup.88--; [0173] wherein each B.sup.8
is independently selected from a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.3-C.sub.6
cycloalkyl or phenyl group, or a 4- to 6-membered heterocyclic
group containing one or two ring heteroatoms N and/or O, or two
B.sup.8 together with the nitrogen atom to which they are attached
may form a 4- to 6-membered heterocyclic group containing one or
two ring heteroatoms N and/or O, wherein any B.sup.8 may optionally
be halo-substituted and/or substituted with one or two substituents
independently selected from --OH, --NH.sub.2, --OB.sup.89,
--NHB.sup.89 or --N(B.sup.89).sub.2; [0174] wherein each B.sup.88
is independently selected from a C.sub.1-C.sub.8 alkylene or
C.sub.2-C.sub.8 alkenylene group, wherein one or two carbon atoms
in the backbone of the alkylene or alkenylene group may optionally
be replaced by one or two heteroatoms N and/or O, and wherein the
alkylene or alkenylene group may optionally be halo-substituted
and/or substituted with one or two substituents independently
selected from --OH, --NH.sub.2, --OB.sup.89, --NHB.sup.89 or
--N(B.sup.89).sub.2; and [0175] wherein each B.sup.89 is
independently selected from a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group.
[0176] Typically, any divalent group --B.sup.88-- forms a 4- to
6-membered fused ring. Typically, the optional substituents on the
heterocyclic or aromatic group are independently selected from
halo, --OH, --NH.sub.2, --CN, --NO.sub.2, --B.sup.8, --OB.sup.8,
--NHB.sup.8 or --N(B.sup.8).sub.2, wherein each B.sup.8 is
independently selected from a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4 alkynyl group all of
which may optionally be halo-substituted. Typically, the optional
substituents on the heterocyclic or aromatic group are selected
from halo, --OH, --NH.sub.2, --CN, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
haloalkyl, --OB.sup.8 or --N(B.sup.8).sub.2, wherein B.sup.8 is
independently selected from C.sub.1-C.sub.4 alkyl which may
optionally be halo-substituted.
[0177] Typically, --R.sup.2 has a formula selected from:
##STR00026##
[0178] wherein R.sup.8 is a 5- or 6-membered, optionally
substituted heterocyclic or aromatic group, and R.sup.1 is
hydrogen, halo, --OH, --NO.sub.2, --CN, --R.sup.ii, --OR.sup.ii,
--COR.sup.ii, --COOR.sup.ii, --CONH.sub.2, --CONHR.sup.ii or
--CON(R.sup.ii).sub.2, wherein each --R.sup.ii is independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.3-C.sub.4 cycloalkyl and C.sub.3-C.sub.4 halocycloalkyl. In
one embodiment, the optional substituents on the heterocyclic or
aromatic group are independently selected from halo, --OH,
--NH.sub.2, --CN, --NO.sub.2, --B.sup.9, --OB.sup.9, --NHB.sup.9,
--N(B.sup.9).sub.2, --CONH.sub.2, --CONHB.sup.9,
--CON(B.sup.9).sub.2, --NHCOB.sup.9, --NB.sup.9COB.sup.9, or
--B.sup.99--; [0179] wherein each B.sup.9 is independently selected
from a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.3-C.sub.6 cycloalkyl or phenyl
group, or a 4- to 6-membered heterocyclic group containing one or
two ring heteroatoms N and/or O, or two B.sup.9 together with the
nitrogen atom to which they are attached may form a 4- to
6-membered heterocyclic group containing one or two ring
heteroatoms N and/or O, wherein any B.sup.9 may optionally be
halo-substituted and/or substituted with one or two substituents
independently selected from --OH, --NH.sub.2, --OB.sup.98,
--NHB.sup.98 or --N(B.sup.98); [0180] wherein each B.sup.99 is
independently selected from a C.sub.1-C.sub.8 alkylene or
C.sub.2-C.sub.8 alkenylene group, wherein one or two carbon atoms
in the backbone of the alkylene or alkenylene group may optionally
be replaced by one or two heteroatoms N and/or O, and wherein the
alkylene or alkenylene group may optionally be halo-substituted
and/or substituted with one or two substituents independently
selected from --OH, --NH.sub.2, --OB.sup.98, --NHB.sup.98 or
--N(B.sup.98).sub.2; and [0181] wherein each B.sup.98 is
independently selected from a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group.
[0182] Typically, any divalent group --B.sup.99-- forms a 4- to
6-membered fused ring. Typically, R.sup.1 is hydrogen, halo, --CN,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, cyclopropyl or
halocyclopropyl. More typically, R.sup.1 is hydrogen or halo.
Typically, the optional substituents on the heterocyclic or
aromatic group are independently selected from halo, --OH,
--NH.sub.2, --CN, --NO.sub.2, --B.sup.9, --OB.sup.9, --NHB.sup.9 or
--N(B.sup.9).sub.2, wherein each B.sup.9 is independently selected
from a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl or
C.sub.2-C.sub.4 alkynyl group all of which may optionally be
halo-substituted. Typically, the optional substituents on the
heterocyclic or aromatic group are selected from halo, --OH,
--NH.sub.2, --CN, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl, --OB.sup.9 or
--N(B.sup.9).sub.2, wherein B.sup.9 is independently selected from
C.sub.1-C.sub.4 alkyl which may optionally be halo-substituted.
[0183] In one embodiment, R.sup.2 is phenyl or a 5- or 6-membered
heteroaryl group (such as phenyl, pyridinyl, pyridazinyl,
pyrimidinyl or pyrazinyl); wherein [0184] (i) the phenyl or 5- or
6-membered heteroaryl group is substituted at the a position with a
substituent selected from --R.sup.9, --OR.sup.9 and --COR.sup.9,
wherein R.sup.9 is selected from a C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6
cyclic group and wherein R.sup.9 is optionally substituted with one
or more halo groups; and [0185] optionally the phenyl or 5- or
6-membered heteroaryl group is further substituted at the .alpha.'
position with a substituent selected from --R.sup.14, --OR.sup.14
and --COR.sup.14, wherein R.sup.14 is selected from a
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.14 is
optionally substituted with one or more halo groups; and [0186]
optionally the phenyl or 5- or 6-membered heteroaryl group is
further substituted (typically with one, two or three substituents
independently selected from halo, --NO.sub.2, --CN, --COOR.sup.15,
--CONH.sub.2, --CONHR.sup.15 or --CON(R.sup.15).sub.2, wherein each
--R.sup.15 is independently selected from a C.sub.1-C.sub.4 alkyl
or C.sub.1-C.sub.4 haloalkyl group); or [0187] (ii) the phenyl or
5- or 6-membered heteroaryl group is substituted with a cycloalkyl,
cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring
which is fused to the parent phenyl or 5- or 6-membered heteroaryl
group across the .alpha.,.beta. positions and which is optionally
substituted with one or more halo groups; and [0188] optionally the
phenyl or 5- or 6-membered heteroaryl group is further substituted
at the .alpha.' position with a substituent selected from
--R.sup.9, --OR.sup.9 and --COR.sup.9, wherein R.sup.9 is selected
from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein
R.sup.9 is optionally substituted with one or more halo groups; and
[0189] optionally the phenyl or 5- or 6-membered heteroaryl group
is further substituted (typically with one or two substituents
independently selected from halo, --NO.sub.2, --CN, --COOR.sup.15,
--CONH.sub.2, --CONHR.sup.15 or --CON(R.sup.15).sub.2, wherein each
--R.sup.15 is independently selected from a C.sub.1-C.sub.4 alkyl
or C.sub.1-C.sub.4 haloalkyl group); or [0190] (iii) the phenyl or
5- or 6-membered heteroaryl group is substituted with a first
cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or
heteroaryl ring which is fused to the parent phenyl or 5- or
6-membered heteroaryl group across the .alpha.,.beta. positions and
which is optionally substituted with one or more halo groups; and
[0191] the phenyl or 5- or 6-membered heteroaryl group is
substituted with a second cycloalkyl, cycloalkenyl, non-aromatic
heterocyclic, aryl or heteroaryl ring which is fused to the parent
phenyl or 5- or 6-membered heteroaryl group across the
.alpha.',.beta.' positions and which is optionally substituted with
one or more halo groups; and [0192] optionally the phenyl group is
further substituted (typically with a substituent selected from
halo, --NO.sub.2, --CN, --COOR.sup.15, --CONH.sub.2, --CONHR.sup.15
or --CON(R.sup.15).sub.2, wherein each --R.sup.15 is independently
selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl
group); or [0193] (iv) the phenyl or 5- or 6-membered heteroaryl
group is substituted at the .alpha.-position with a monovalent
heterocyclic group or a monovalent aromatic group selected from
phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or
tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic
group may optionally be substituted with one or two substituents
independently selected from halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, --R.sup.12--OR.sup.13,
--R.sup.12--N(R.sup.13).sub.2, --R.sup.12--CN or
--R.sup.12--C.ident.CR.sup.13, and wherein a ring atom of the
monovalent heterocyclic or aromatic group is directly attached to
the .alpha.-ring atom of the parent phenyl or 5- or 6-membered
heteroaryl group; wherein R.sup.12 is independently selected from a
bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.13 is
independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group; and [0194] optionally the phenyl
or 5- or 6-membered heteroaryl group is further substituted at the
.alpha.' position with a substituent selected from --R.sup.9,
--OR.sup.9 and --COR.sup.9, wherein R.sup.9 is selected from a
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.9 is
optionally substituted with one or more halo groups; and [0195]
optionally the phenyl or 5- or 6-membered heteroaryl group is
further substituted (typically with one, two or three substituents
independently selected from halo, --NO.sub.2, --CN, --COOR.sup.15,
--CONH.sub.2, --CONHR.sup.15 or --CON(R.sup.15).sub.2, wherein each
--R.sup.15 is independently selected from a C.sub.1-C.sub.4 alkyl
or C.sub.1-C.sub.4 haloalkyl group); or [0196] (v) the phenyl or 5-
or 6-membered heteroaryl group is substituted at the
.alpha.-position with a monovalent heterocyclic group or a
monovalent aromatic group selected from phenyl, pyridinyl,
pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl,
wherein the monovalent heterocyclic or aromatic group may
optionally be substituted with one or two substituents
independently selected from halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, --R.sup.12--OR.sup.13,
--R.sup.12--N(R.sup.13).sub.2, --R.sup.12--CN or
--R.sup.12--C.ident.CR.sup.13, and wherein a ring atom of the
monovalent heterocyclic or aromatic group is directly attached to
the .alpha.-ring atom of the parent phenyl or 5- or 6-membered
heteroaryl group; wherein R.sup.12 is independently selected from a
bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.13 is
independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group; and [0197] optionally the phenyl
or 5- or 6-membered heteroaryl group is further substituted with a
cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or
heteroaryl ring which is fused to the parent phenyl or 5- or
6-membered heteroaryl group across the .alpha.',.beta.' positions
and which is optionally substituted with one or more halo groups;
and [0198] optionally the phenyl or 5- or 6-membered heteroaryl
group is further substituted (typically with one or two
substituents independently selected from halo, --NO.sub.2, --CN,
--COOR.sup.15, --CONH.sub.2, --CONHR.sup.15 or
--CON(R.sup.15).sub.2, wherein each --R.sup.15 is independently
selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl
group).
[0199] In the embodiment directly above, where a group or moiety is
optionally substituted with one or more halo groups, it may be
substituted for example with one, two, three, four, five or six
halo groups.
[0200] In one aspect of any of the above embodiments, R.sup.2
contains from 15 to 50 atoms. More typically, R.sup.2 contains from
20 to 40 atoms. Most typically, R.sup.2 contains from 25 to 35
atoms.
[0201] In another aspect of any of the above embodiments, R.sup.2
contains from 10 to 50 atoms other than hydrogen. More typically,
R.sup.2 contains from 10 to 40 atoms other than hydrogen. More
typically, R.sup.2 contains from 10 to 35 atoms other than
hydrogen. Most typically, R.sup.2 contains from 12 to 30 atoms
other than hydrogen.
[0202] In one embodiment, R.sup.1 is a saturated or unsaturated
C.sub.1-C.sub.15 hydrocarbyl group, wherein the hydrocarbyl group
may be straight-chained or branched, or be or include cyclic
groups, wherein the hydrocarbyl group may optionally be
substituted, and wherein the atom of R.sup.1 which is attached to
the sulfur atom of the sulfonylurea group is not a ring atom of a
cyclic group; and R.sup.2 is a cyclic group substituted at the
.alpha. and .alpha.' positions, wherein R.sup.2 may optionally be
further substituted.
[0203] In another embodiment, R.sup.2 is a fused cyclic group,
wherein a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl
or heteroaryl ring is fused to the cyclic group across the
.alpha.,.beta. positions, wherein R.sup.2 is further substituted at
the .alpha.' position, and wherein R.sup.2 may optionally be
further substituted.
[0204] In another embodiment, R.sup.2 is a fused cyclic group,
wherein a first cycloalkyl, cycloalkenyl, non-aromatic
heterocyclic, aryl or heteroaryl ring is fused to the cyclic group
across the .alpha.,.beta. positions and a second cycloalkyl,
cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is
fused to the cyclic group across the .alpha.',.beta.' positions,
and wherein R.sup.2 may optionally be further substituted.
[0205] Q is selected from O or S. In one embodiment of the first
aspect of the invention, Q is O.
[0206] In one embodiment, the invention provides a compound of
formula (I), wherein: [0207] Q is O; [0208] R.sup.1 is a saturated
or unsaturated C.sub.1-C.sub.12 hydrocarbyl group, wherein the
hydrocarbyl group may be straight-chained or branched, or be or
include cyclic groups, wherein the hydrocarbyl group may optionally
be substituted with one, two or three substituents independently
selected from halo, C.sub.1-C.sub.4 haloalkyl, --CN, --N.sub.3,
--NO.sub.2, --OH, --SR.sup..delta., --SOR.sup..delta.,
--SO.sub.2R.sup..delta., --SO.sub.2N(R.sup..delta.).sub.2,
--NH.sub.2, --COR.sup..delta., --COOR.sup..delta. or
--OCOR.sup..delta., wherein each --R.sup..delta. is independently
selected from hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl or
C.sub.3-C.sub.7 cycloalkyl group, and wherein the atom of R.sup.1
which is attached to the sulfur atom of the sulfonylurea group is
not a ring atom of a cyclic group; and [0209] R.sup.2 is a cyclic
group substituted at the .alpha.-position, wherein R.sup.2 may
optionally be further substituted. In one embodiment, R.sup.2 is a
cyclic group substituted at the .alpha. and .alpha.' positions.
[0210] In another embodiment, the invention provides a compound of
formula (I), wherein: [0211] Q is O; [0212] R.sup.1 is a saturated
or unsaturated C.sub.1-C.sub.8 hydrocarbyl group, wherein the
hydrocarbyl group may be straight-chained or branched, but may not
be or include cyclic groups, wherein the hydrocarbyl group may
optionally be substituted with one, two or three substituents
independently selected from halo, C.sub.1-C.sub.4 haloalkyl, --CN,
--N.sub.3, --SR.sup..delta., --SOR.sup..delta.,
--SO.sub.2R.sup..delta. or --SO.sub.2N(R.sup..delta.).sub.2,
wherein each --R.sup..delta. is independently selected from
hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl or
C.sub.3-C.sub.7 cycloalkyl group, and wherein the atom of R.sup.1
which is attached to the sulfur atom of the sulfonylurea group is
not a ring atom of a cyclic group; and [0213] R.sup.2 is a cyclic
group substituted at the a position, wherein R.sup.2 may optionally
be further substituted. In one embodiment, R.sup.2 is a cyclic
group substituted at the .alpha. and .alpha.' positions.
[0214] In another embodiment, the invention provides a compound of
formula (I), wherein: [0215] Q is O; [0216] --R.sup.1 is
--(CHR.sup.4).sub.nR.sup.3; wherein n is 1, 2 or 3; R.sup.4 is
independently selected from hydrogen, methyl or ethyl; and R.sup.3
is a branched or cyclic C.sub.1-C.sub.(12-n) hydrocarbyl group,
wherein the hydrocarbyl group may optionally be substituted with
one, two or three substituents independently selected from halo,
C.sub.1-C.sub.4 haloalkyl, --CN, --N.sub.3, --NO.sub.2, --OH,
--SR.sup..delta., --SOR.sup..delta., --SO.sub.2R.sup..delta.,
--SO.sub.2N(R.sup..delta.).sub.2, --NH.sub.2, --COR.sup..delta.,
--COOR.sup..delta. or --OCOR.sup..delta., wherein each
--R.sup..delta. is independently selected from hydrogen or a
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4
alkynyl, C.sub.1-C.sub.4 haloalkyl or C.sub.3-C.sub.7 cycloalkyl
group; and [0217] R.sup.2 is a cyclic group substituted at the
.alpha.-position, wherein R.sup.2 may optionally be further
substituted. In one embodiment, R.sup.4 is hydrogen. In one
embodiment, R.sup.2 is a cyclic group substituted at the .alpha.
and .alpha.' positions.
[0218] In another embodiment, the invention provides a compound of
formula (I), wherein: [0219] Q is O; [0220] --R.sup.1 is
--(CHR.sup.4).sub.nR.sup.3; wherein n is 1, 2 or 3; R.sup.4 is
independently selected from hydrogen, methyl or ethyl; and R.sup.3
is a branched or cyclic C.sub.1-C.sub.(10-n) hydrocarbyl group,
wherein the hydrocarbyl group may optionally be substituted with
one, two or three substituents independently selected from halo,
C.sub.1-C.sub.4 haloalkyl, --CN, --N.sub.3, --SR.sup.8,
--SOR.sup..delta., --SO.sub.2R.sup..delta. or
--SO.sub.2N(R.sup..delta.).sub.2, wherein each --R.sup..delta. is
independently selected from hydrogen or a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
haloalkyl or C.sub.3-C.sub.7 cycloalkyl group; and [0221] R.sup.2
is a cyclic group substituted at the a position, wherein R.sup.2
may optionally be further substituted. In one embodiment, R.sup.4
is hydrogen. In one embodiment, R.sup.2 is a cyclic group
substituted at the .alpha. and .alpha.' positions.
[0222] In another embodiment, the invention provides a compound of
formula (I), wherein: [0223] Q is O; [0224] --R.sup.1 is
--(CHR.sup.4).sub.nR.sup.3; wherein n is 1, 2 or 3; R.sup.4 is
independently selected from hydrogen, methyl or ethyl; and R.sup.3
is phenyl optionally substituted with one, two or three
substituents independently selected from halo, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, --CN, --N.sub.3, --NO.sub.2,
--OR.sup..delta., --SR.sup..delta., --SOR.sup..delta.,
--SO.sub.2R.sup..delta., --SO.sub.2N(R.sup..delta.).sub.2,
--NH.sub.2, --COR.sup..delta., --COOR.sup..delta. or
--OCOR.sup..delta., wherein each --R.sup..delta. is independently
selected from hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 haloalkyl or
C.sub.3-C.sub.7 cycloalkyl group; and [0225] R.sup.2 is a cyclic
group substituted at the a position, wherein R.sup.2 may optionally
be further substituted. In one embodiment, R.sup.4 is hydrogen. In
one embodiment, R.sup.2 is a cyclic group substituted at the
.alpha. and .alpha.' positions.
[0226] In a first specific embodiment, the invention provides a
compound of formula (I), wherein: [0227] Q is O; [0228] R.sup.1 is
selected from: [0229] (a) a branched C.sub.3-C.sub.7 alkyl
(preferably C.sub.4-C.sub.7 alkyl) group, wherein the alkyl group
is unsubstituted; or [0230] (b) a straight-chained C.sub.2-C.sub.7
alkenyl (preferably C.sub.2 alkenyl or C.sub.4-C.sub.7 alkenyl)
group, wherein the alkenyl group is unsubstituted; or [0231] (c)
--(C(R.sup.4).sub.2).sub.nR.sup.3; wherein n is 1 or 2; each
R.sup.4 is independently selected from hydrogen, halo, methyl or
halomethyl; and R.sup.3 is a phenyl group, wherein the phenyl group
may optionally be halo substituted and/or may optionally be
substituted with one or two substituents independently selected
from C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, --CN,
--OR.sup..delta., --COR.sup..delta., or --COOR.sup..delta., wherein
each --R.sup..delta. is independently selected from hydrogen or a
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, cyclopropyl or
halocyclopropyl group, and wherein the group --R.sup.1 including
any optional substituents contains from 7 to 12 carbon atoms; or
[0232] (d) a C.sub.1-C.sub.6 alkyl (preferably C.sub.2-C.sub.6
alkyl or C.sub.3-C.sub.6 alkyl) or C.sub.2-C.sub.6 alkenyl group,
wherein the alkyl or alkenyl group is halo substituted and/or is
substituted with one, two or three substituents independently
selected from --CN, --N.sub.3, --NO.sub.2, --OR.sup..delta.,
--N(R.sup..delta.).sub.2, --COR.sup..delta. or --COOR.sup..delta.,
wherein each --R.sup..delta. is independently selected from
hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.3-C.sub.7 cycloalkyl or C.sub.3-C.sub.7 halocycloalkyl group;
and wherein: [0233] R.sup.2 is phenyl or a 5- or 6-membered
heteroaryl group; wherein [0234] (i) the phenyl or 5- or 6-membered
heteroaryl group is substituted at the a position with a
substituent selected from --R.sup.9, --OR.sup.9 and --COR.sup.9,
wherein R.sup.9 is selected from a C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6
cyclic group and wherein R.sup.9 is optionally substituted with one
or more halo groups; and [0235] optionally the phenyl or 5- or
6-membered heteroaryl group is further substituted at the .alpha.'
position with a substituent selected from --R.sup.14, --OR.sup.14
and --COR.sup.14, wherein R.sup.14 is selected from a
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.14 is
optionally substituted with one or more halo groups; and [0236]
optionally the phenyl or 5- or 6-membered heteroaryl group is
further substituted (typically with one, two or three substituents
independently selected from halo, --NO.sub.2, --CN, --COOR.sup.15,
--CONH.sub.2, --CONHR.sup.15 or --CON(R.sup.15).sub.2, wherein each
--R.sup.15 is independently selected from a C.sub.1-C.sub.4 alkyl
or C.sub.1-C.sub.4 haloalkyl group); or [0237] (ii) the phenyl or
5- or 6-membered heteroaryl group is substituted with a cycloalkyl,
cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring
which is fused to the parent phenyl or 5- or 6-membered heteroaryl
group across the .alpha.,.beta. positions and which is optionally
substituted with one or more halo groups; and [0238] optionally the
phenyl or 5- or 6-membered heteroaryl group is further substituted
at the .alpha.' position with a substituent selected from
--R.sup.9, --OR.sup.9 and --COR.sup.9, wherein R.sup.9 is selected
from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein
R.sup.9 is optionally substituted with one or more halo groups; and
[0239] optionally the phenyl or 5- or 6-membered heteroaryl group
is further substituted (typically with one or two substituents
independently selected from halo, --NO.sub.2, --CN, --COOR.sup.15,
--CONH.sub.2, --CONHR.sup.15 or --CON(R.sup.15).sub.2, wherein each
--R.sup.15 is independently selected from a C.sub.1-C.sub.4 alkyl
or C.sub.1-C.sub.4 haloalkyl group); or [0240] (iii) the phenyl or
5- or 6-membered heteroaryl group is substituted with a first
cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or
heteroaryl ring which is fused to the parent phenyl or 5- or
6-membered heteroaryl group across the .alpha.,.beta. positions and
which is optionally substituted with one or more halo groups; and
[0241] the phenyl or 5- or 6-membered heteroaryl group is
substituted with a second cycloalkyl, cycloalkenyl, non-aromatic
heterocyclic, aryl or heteroaryl ring which is fused to the parent
phenyl or 5- or 6-membered heteroaryl group across the
.alpha.',.beta.' positions and which is optionally substituted with
one or more halo groups; and [0242] optionally the phenyl group is
further substituted (typically with a substituent selected from
halo, --NO.sub.2, --CN, --COOR.sup.15, --CONH.sub.2, --CONHR.sup.15
or --CON(R.sup.15).sub.2, wherein each --R.sup.15 is independently
selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl
group); or [0243] (iv) the phenyl or 5- or 6-membered heteroaryl
group is substituted at the .alpha.-position with a monovalent
heterocyclic group or a monovalent aromatic group selected from
phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or
tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic
group may optionally be substituted with one or two substituents
independently selected from halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, --R.sup.12--OR.sup.13,
--R.sup.12--N(R.sup.13).sub.2, --R.sup.12--CN or
--R.sup.12--C.ident.CR.sup.13, and wherein a ring atom of the
monovalent heterocyclic or aromatic group is directly attached to
the .alpha.-ring atom of the parent phenyl or 5- or 6-membered
heteroaryl group; wherein R.sup.12 is independently selected from a
bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.13 is
independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group; and [0244] optionally the phenyl
or 5- or 6-membered heteroaryl group is further substituted at the
.alpha.' position with a substituent selected from --R.sup.9,
--OR.sup.9 and --COR.sup.9, wherein R.sup.9 is selected from a
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.9 is
optionally substituted with one or more halo groups; and [0245]
optionally the phenyl or 5- or 6-membered heteroaryl group is
further substituted (typically with one, two or three substituents
independently selected from halo, --NO.sub.2, --CN, --COOR.sup.15,
--CONH.sub.2, --CONHR.sup.15 or --CON(R.sup.15).sub.2, wherein each
--R.sup.15 is independently selected from a C.sub.1-C.sub.4 alkyl
or C.sub.1-C.sub.4 haloalkyl group); or [0246] (v) the phenyl or 5-
or 6-membered heteroaryl group is substituted at the
.alpha.-position with a monovalent heterocyclic group or a
monovalent aromatic group selected from phenyl, pyridinyl,
pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl,
wherein the monovalent heterocyclic or aromatic group may
optionally be substituted with one or two substituents
independently selected from halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, --R.sup.12--OR.sup.13,
--R.sup.12--N(R.sup.13).sub.2, --R.sup.12--CN or
--R.sup.12--C.ident.CR.sup.13, and wherein a ring atom of the
monovalent heterocyclic or aromatic group is directly attached to
the .alpha.-ring atom of the parent phenyl or 5- or 6-membered
heteroaryl group; wherein R.sup.12 is independently selected from a
bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.13 is
independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group; and [0247] optionally the phenyl
or 5- or 6-membered heteroaryl group is further substituted with a
cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or
heteroaryl ring which is fused to the parent phenyl or 5- or
6-membered heteroaryl group across the .alpha.',.beta.' positions
and which is optionally substituted with one or more halo groups;
and [0248] optionally the phenyl or 5- or 6-membered heteroaryl
group is further substituted (typically with one or two
substituents independently selected from halo, --NO.sub.2, --CN,
--COOR.sup.15, --CONH.sub.2, --CONHR.sup.15 or
--CON(R.sup.15).sub.2, wherein each --R.sup.15 is independently
selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl
group).
[0249] In this first specific embodiment, the parent phenyl or 5-
or 6-membered heteroaryl group of R.sup.2 may be selected from
phenyl, pyridinyl (such as pyridin-3-yl or pyridin-4-yl),
pyridazinyl, pyrimidinyl (such as pyrimidin-2-yl or
pyrimidin-5-yl), pyrazinyl, pyrrolyl, furanyl, thiophenyl,
pyrazolyl (such as pyrazol-1-yl, pyrazol-3-yl or pyrazol-4-yl),
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
triazolyl or oxadiazolyl. Typically, the parent phenyl or 5- or
6-membered heteroaryl group of R.sup.2 may be selected from phenyl,
pyridinyl (such as pyridin-3-yl or pyridin-4-yl), pyridazinyl,
pyrimidinyl (such as pyrimidin-2-yl or pyrimidin-5-yl) or
pyrazinyl. Typically, the parent phenyl or 5- or 6-membered
heteroaryl group of R.sup.2 may be phenyl.
[0250] In this first specific embodiment, where a group or moiety
is optionally substituted with one or more halo groups, it may be
substituted for example with one, two, three, four, five or six
halo groups.
[0251] Typically in this first specific embodiment, the compound is
not:
##STR00027##
[0252] In a second specific embodiment, the invention provides a
compound of formula (I),
[0253] wherein: [0254] Q is O; [0255] R.sup.1 is selected from:
[0256] (a) a C.sub.1-C.sub.7 alkyl or C.sub.2-C.sub.7 alkenyl
group, wherein the alkyl or alkenyl group is unsubstituted; or
[0257] (b) a C.sub.1-C.sub.6 alkyl or C.sub.2-C.sub.6 alkenyl
group, wherein the alkyl or alkenyl group is halo substituted
and/or is substituted with one, two or three substituents
independently selected from --CN, --N.sub.3, --NO.sub.2,
--OR.sup..delta., --N(R.sup..delta.).sub.2, --COR.sup..delta. or
--COOR.sup..delta., wherein each --R.sup..delta. is independently
selected from hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.3-C.sub.7
halocycloalkyl group;
[0258] and wherein: [0259] R.sup.2 is phenyl or a 5- or 6-membered
heteroaryl group; wherein [0260] (i) the phenyl or 5- or 6-membered
heteroaryl group is substituted at the .alpha.-position with a
monovalent heterocyclic group or a monovalent aromatic group
selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl,
imidazolyl, triazolyl or tetrahydropyranyl, wherein the monovalent
heterocyclic or aromatic group may optionally be substituted with
one or two substituents independently selected from halo,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl,
--R.sup.12--OR.sup.13, --R.sup.12--N(R.sup.13).sub.2,
--R.sup.12--CN or --R.sup.12--C.ident.CR.sup.13, and wherein a ring
atom of the monovalent heterocyclic or aromatic group is directly
attached to the .alpha.-ring atom of the parent phenyl or 5- or
6-membered heteroaryl group; wherein R.sup.12 is independently
selected from a bond or a C.sub.1-C.sub.3 alkylene group; and
R.sup.13 is independently selected from hydrogen or a
C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl group; and
[0261] optionally the phenyl or 5- or 6-membered heteroaryl group
is further substituted at the .alpha.' position with a substituent
selected from --R.sup.9, --OR.sup.9 and --COR.sup.9, wherein
R.sup.9 is selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group
and wherein R.sup.9 is optionally substituted with one or more halo
groups; and optionally the phenyl or 5- or 6-membered heteroaryl
group is further substituted (typically with one, two or three
substituents independently selected from halo, --NO.sub.2, --CN,
--COOR.sup.15, --CONH.sub.2, --CONHR.sup.15 or
--CON(R.sup.15).sub.2, wherein each --R.sup.15 is independently
selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl
group); or [0262] (ii) the phenyl or 5- or 6-membered heteroaryl
group is substituted at the .alpha.-position with a monovalent
heterocyclic group or a monovalent aromatic group selected from
phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or
tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic
group may optionally be substituted with one or two substituents
independently selected from halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, --R.sup.12--OR.sup.13,
--R.sup.12--N(R.sup.13).sub.2, --R.sup.12--CN or
--R.sup.12--C.ident.CR.sup.13, and wherein a ring atom of the
monovalent heterocyclic or aromatic group is directly attached to
the .alpha.-ring atom of the parent phenyl or 5- or 6-membered
heteroaryl group; wherein R.sup.12 is independently selected from a
bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.13 is
independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl group; and [0263] optionally the phenyl
or 5- or 6-membered heteroaryl group is further substituted with a
cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or
heteroaryl ring which is fused to the parent phenyl or 5- or
6-membered heteroaryl group across the .alpha.',.beta.' positions
and which is optionally substituted with one or more halo groups;
and [0264] optionally the phenyl or 5- or 6-membered heteroaryl
group is further substituted (typically with one or two
substituents independently selected from halo, --NO.sub.2, --CN,
--COOR.sup.15, --CONH.sub.2, --CONHR.sup.15 or
--CON(R.sup.15).sub.2, wherein each --R.sup.15 is independently
selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl
group).
[0265] In this second specific embodiment, the parent phenyl or 5-
or 6-membered heteroaryl group of R.sup.2 may be selected from
phenyl, pyridinyl (such as pyridin-3-yl or pyridin-4-yl),
pyridazinyl, pyrimidinyl (such as pyrimidin-2-yl or
pyrimidin-5-yl), pyrazinyl, pyrrolyl, furanyl, thiophenyl,
pyrazolyl (such as pyrazol-1-yl, pyrazol-3-yl or pyrazol-4-yl),
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
triazolyl or oxadiazolyl. Typically, the parent phenyl or 5- or
6-membered heteroaryl group of R.sup.2 may be selected from phenyl,
pyridinyl (such as pyridin-3-yl or pyridin-4-yl), pyridazinyl,
pyrimidinyl (such as pyrimidin-2-yl or pyrimidin-5-yl) or
pyrazinyl. Typically, the parent phenyl or 5- or 6-membered
heteroaryl group of R.sup.2 may be phenyl.
[0266] In this second specific embodiment, where a group or moiety
is optionally substituted with one or more halo groups, it may be
substituted for example with one, two, three, four, five or six
halo groups.
[0267] In one aspect of any of the above embodiments, the compound
of formula (I) has a molecular weight of from 200 to 2,000 Da.
Typically, the compound of formula (I) has a molecular weight of
from 230 to 900 Da. Typically, the compound of formula (I) has a
molecular weight of from 260 to 60000 Da. More typically, the
compound of formula (I) has a molecular weight of from 280 to 480
Da.
[0268] A second aspect of the invention provides a compound
selected from the group consisting of:
##STR00028## ##STR00029## ##STR00030## ##STR00031##
[0269] A third aspect of the invention provides a pharmaceutically
acceptable salt, solvate or prodrug of any compound of the first or
second aspect of the invention.
[0270] The compounds of the present invention can be used both in
their free base form and their acid addition salt form. For the
purposes of this invention, a "salt" of a compound of the present
invention includes an acid addition salt. Acid addition salts are
preferably pharmaceutically acceptable, non-toxic addition salts
with suitable acids, including but not limited to inorganic acids
such as hydrohalogenic acids (for example, hydrofluoric,
hydrochloric, hydrobromic or hydroiodic acid) or other inorganic
acids (for example, nitric, perchloric, sulfuric or phosphoric
acid); or organic acids such as organic carboxylic acids (for
example, propionic, butyric, glycolic, lactic, mandelic, citric,
acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic,
tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric,
gluconic, pantothenic or pamoic acid), organic sulfonic acids (for
example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic,
2-hydroxyethanesulfonic, benzenesulfonic, toluene-p-sulfonic,
naphthalene-2-sulfonic or camphorsulfonic acid) or amino acids (for
example, ornithinic, glutamic or aspartic acid). The acid addition
salt may be a mono-, di-, tri- or multi-acid addition salt. A
preferred salt is a hydrohalogenic, sulfuric, phosphoric or organic
acid addition salt. A preferred salt is a hydrochloric acid
addition salt.
[0271] Where a compound of the invention includes a quaternary
ammonium group, typically the compound is used in its salt form.
The counter ion to the quaternary ammonium group may be any
pharmaceutically acceptable, non-toxic counter ion. Examples of
suitable counter ions include the conjugate bases of the protic
acids discussed above in relation to acid-addition salts.
[0272] The compounds of the present invention can also be used
both, in their free acid form and their salt form. For the purposes
of this invention, a "salt" of a compound of the present invention
includes one formed between a protic acid functionality (such as a
carboxylic acid group) of a compound of the present invention and a
suitable cation. Suitable cations include, but are not limited to
lithium, sodium, potassium, magnesium, calcium and ammonium. The
salt may be a mono-, di-, tri- or multi-salt. Preferably the salt
is a mono- or di-lithium, sodium, potassium, magnesium, calcium or
ammonium salt. More preferably the salt is a mono- or di-sodium
salt or a mono- or di-potassium salt.
[0273] Preferably any salt is a pharmaceutically acceptable
non-toxic salt. However, in addition to pharmaceutically acceptable
salts, other salts are included in the present invention, since
they have potential to serve as intermediates in the purification
or preparation of other, for example, pharmaceutically acceptable
salts, or are useful for identification, characterisation or
purification of the free acid or base.
[0274] The compounds and/or salts of the present invention may be
anhydrous or in the form of a hydrate (e.g. a hemihydrate,
monohydrate, dihydrate or trihydrate) or other solvate. Such
solvates may be formed with common organic solvents, including but
not limited to, alcoholic solvents e.g. methanol, ethanol or
isopropanol.
[0275] In some embodiments of the present invention,
therapeutically inactive prodrugs are provided. Prodrugs are
compounds which, when administered to a subject such as a human,
are converted in whole or in part to a compound of the invention.
In most embodiments, the prodrugs are pharmacologically inert
chemical derivatives that can be converted in vivo to the active
drug molecules to exert a therapeutic effect. Any of the compounds
described herein can be administered as a prodrug to increase the
activity, bioavailability, or stability of the compound or to
otherwise alter the properties of the compound. Typical examples of
prodrugs include compounds that have biologically labile protecting
groups on a functional moiety of the active compound. Prodrugs
include, but are not limited to, compounds that can be oxidized,
reduced, aminated, deaminated, hydroxylated, dehydroxylated,
hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated,
deacylated, phosphorylated, and/or dephosphorylated to produce the
active compound. The present invention also encompasses salts and
solvates of such prodrugs as described above.
[0276] The compounds, salts, solvates and prodrugs of the present
invention may contain at least one chiral centre. The compounds,
salts, solvates and prodrugs may therefore exist in at least two
isomeric forms. The present invention encompasses racemic mixtures
of the compounds, salts, solvates and prodrugs of the present
invention as well as enantiomerically enriched and substantially
enantiomerically pure isomers. For the purposes of this invention,
a "substantially enantiomerically pure" isomer of a compound
comprises less than 5% of other isomers of the same compound, more
typically less than 2%, and most typically less than 0.5% by
weight.
[0277] The compounds, salts, solvates and prodrugs of the present
invention may contain any stable isotope including, but not limited
to .sup.12C, .sup.13C, .sup.1H, .sup.2H (D), .sup.14N, .sup.15N,
.sup.16O, .sup.17O, .sup.18O, .sup.19F and .sup.127I, and any
radioisotope including, but not limited to .sup.11C, .sup.14C,
.sup.3H (T), .sup.13N, .sup.15O, .sup.18F, .sup.123J, .sup.124J,
.sup.125I and .sup.131I.
[0278] The compounds, salts, solvates and prodrugs of the present
invention may be in any polymorphic or amorphous form.
[0279] A fourth aspect of the invention provides a pharmaceutical
composition comprising a compound of the first or second aspect of
the invention, or a pharmaceutically acceptable salt, solvate or
prodrug of the third aspect of the invention, and a
pharmaceutically acceptable excipient.
[0280] Conventional procedures for the selection and preparation of
suitable pharmaceutical formulations are described in, for example,
"Aulton's Pharmaceutics--The Design and Manufacture of Medicines",
M. E. Aulton and K. M. G. Taylor, Churchill Livingstone Elsevier,
4.sup.th Ed., 2013.
[0281] Pharmaceutically acceptable excipients including adjuvants,
diluents or carriers that may be used in the pharmaceutical
compositions of the invention are those conventionally employed in
the field of pharmaceutical formulation, and include, but are not
limited to, sugars, sugar alcohols, starches, ion exchangers,
alumina, aluminium stearate, lecithin, serum proteins such as human
serum albumin, buffer substances such as phosphates, glycerine,
sorbic acid, potassium sorbate, partial glyceride mixtures of
saturated vegetable fatty acids, water, salts or electrolytes such
as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium trisilicate, polyvinylpyrrolidone, cellulose-based
substances, polyethylene glycol, sodium carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.
[0282] In one embodiment, the pharmaceutical composition of the
fourth aspect of the invention is a topical pharmaceutical
composition. For example, the topical pharmaceutical composition
may be a dermal pharmaceutical composition or an ocular
pharmaceutical composition.
[0283] In one embodiment, the pharmaceutical composition of the
fourth aspect of the invention additionally comprises one or more
further active agents.
[0284] In a further embodiment, the pharmaceutical composition of
the fourth aspect of the invention may be provided as a part of a
kit of parts, wherein the kit of parts comprises the pharmaceutical
composition of the fourth aspect of the invention and one or more
further pharmaceutical compositions, wherein the one or more
further pharmaceutical compositions each comprise a
pharmaceutically acceptable excipient and one or more further
active agents.
[0285] A fifth aspect of the invention provides a compound of the
first or second aspect of the invention, or a pharmaceutically
acceptable salt, solvate or prodrug of the third aspect of the
invention, or a pharmaceutical composition of the fourth aspect of
the invention, for use in medicine, and/or for use in the treatment
or prevention of a disease, disorder or condition. Typically the
use comprises the administration of the compound, salt, solvate,
prodrug or pharmaceutical composition to a subject. In one
embodiment, the use comprises the co-administration of one or more
further active agents.
[0286] The term "treatment" as used herein refers equally to
curative therapy, and ameliorating or palliative therapy. The term
includes obtaining beneficial or desired physiological results,
which may or may not be established clinically. Beneficial or
desired clinical results include, but are not limited to, the
alleviation of symptoms, the prevention of symptoms, the
diminishment of extent of disease, the stabilisation (i.e., not
worsening) of a condition, the delay or slowing of
progression/worsening of a condition/symptoms, the amelioration or
palliation of the condition/symptoms, and remission (whether
partial or total), whether detectable or undetectable. The term
"palliation", and variations thereof, as used herein, means that
the extent and/or undesirable manifestations of a physiological
condition or symptom are lessened and/or time course of the
progression is slowed or lengthened, as compared to not
administering a compound, salt, solvate, prodrug or pharmaceutical
composition of the present invention. The term "prevention" as used
herein in relation to a disease, disorder or condition, relates to
prophylactic or preventative therapy, as well as therapy to reduce
the risk of developing the disease, disorder or condition. The term
"prevention" includes both the avoidance of occurrence of the
disease, disorder or condition, and the delay in onset of the
disease, disorder or condition. Any statistically significant
(p.ltoreq.0.05) avoidance of occurrence, delay in onset or
reduction in risk as measured by a controlled clinical trial may be
deemed a prevention of the disease, disorder or condition. Subjects
amenable to prevention include those at heightened risk of a
disease, disorder or condition as identified by genetic or
biochemical markers. Typically, the genetic or biochemical markers
are appropriate to the disease, disorder or condition under
consideration and may include for example, inflammatory biomarkers
such as C-reactive protein (CRP) and monocyte chemoattractant
protein 1 (MCP-1) in the case of inflammation; total cholesterol,
triglycerides, insulin resistance and C-peptide in the case of
NAFLD and NASH; and more generally IL1.beta. and IL18 in the case
of a disease, disorder or condition responsive to NLRP3
inhibition.
[0287] A sixth aspect of the invention provides the use of a
compound of the first or second aspect, or a pharmaceutically
effective salt, solvate or prodrug of the third aspect, in the
manufacture of a medicament for the treatment or prevention of a
disease, disorder or condition. Typically the treatment or
prevention comprises the administration of the compound, salt,
solvate, prodrug or medicament to a subject. In one embodiment, the
treatment or prevention comprises the co-administration of one or
more further active agents.
[0288] A seventh aspect of the invention provides a method of
treatment or prevention of a disease, disorder or condition, the
method comprising the step of administering an effective amount of
a compound of the first or second aspect, or a pharmaceutically
acceptable salt, solvate or prodrug of the third aspect, or a
pharmaceutical composition of the fourth aspect, to thereby treat
or prevent the disease, disorder or condition. In one embodiment,
the method further comprises the step of co-administering an
effective amount of one or more further active agents. Typically,
the administration is to a subject in need thereof.
[0289] An eighth aspect of the invention provides a compound of the
first or second aspect of the invention, or a pharmaceutically
acceptable salt, solvate or prodrug of the third aspect of the
invention, or a pharmaceutical composition of the fourth aspect of
the invention, for use in the treatment or prevention of a disease,
disorder or condition in an individual, wherein the individual has
a germline or somatic non-silent mutation in NLRP3. The mutation
may be, for example, a gain-of-function or other mutation resulting
in increased NLRP3 activity. Typically, the use comprises the
administration of the compound, salt, solvate, prodrug or
pharmaceutical composition to the individual. In one embodiment,
the use comprises the co-administration of one or more further
active agents. The use may also comprise the diagnosis of an
individual having a germline or somatic non-silent mutation in
NLRP3, wherein the compound, salt, solvate, prodrug or
pharmaceutical composition is administered to an individual on the
basis of a positive diagnosis for the mutation. Typically,
identification of the mutation in NLRP3 in the individual may be by
any suitable genetic or biochemical means.
[0290] A ninth aspect of the invention provides the use of a
compound of the first or second aspect, or a pharmaceutically
effective salt, solvate or prodrug of the third aspect, in the
manufacture of a medicament for the treatment or prevention of a
disease, disorder or condition in an individual, wherein the
individual has a germline or somatic non-silent mutation in NLRP3.
The mutation may be, for example, a gain-of-function or other
mutation resulting in increased NLRP3 activity. Typically, the
treatment or prevention comprises the administration of the
compound, salt, solvate, prodrug or medicament to the individual.
In one embodiment, the treatment or prevention comprises the
co-administration of one or more further active agents. The
treatment or prevention may also comprise the diagnosis of an
individual having a germline or somatic non-silent mutation in
NLRP3, wherein the compound, salt, solvate, prodrug or medicament
is administered to an individual on the basis of a positive
diagnosis for the mutation. Typically, identification of the
mutation in NLRP3 in the individual may be by any suitable genetic
or biochemical means.
[0291] A tenth aspect of the invention provides a method of
treatment or prevention of a disease, disorder or condition, the
method comprising the steps of diagnosing of an individual having a
germline or somatic non-silent mutation in NLRP3, and administering
an effective amount of a compound of the first or second aspect, or
a pharmaceutically acceptable salt, solvate or prodrug of the third
aspect, or a pharmaceutical composition of the fourth aspect, to
the positively diagnosed individual, to thereby treat or prevent
the disease, disorder or condition. In one embodiment, the method
further comprises the step of co-administering an effective amount
of one or more further active agents. Typically, the administration
is to a subject in need thereof.
[0292] In general embodiments, the disease, disorder or condition
may be a disease, disorder or condition of the immune system, the
cardiovascular system, the endocrine system, the gastrointestinal
tract, the renal system, the hepatic system, the metabolic system,
the respiratory system, the central nervous system, may be a cancer
or other malignancy, and/or may be caused by or associated with a
pathogen.
[0293] It will be appreciated that these general embodiments
defined according to broad categories of diseases, disorders and
conditions are not mutually exclusive. In this regard any
particular disease, disorder or condition may be categorized
according to more than one of the above general embodiments. A
non-limiting example is type I diabetes which is an autoimmune
disease and a disease of the endocrine system.
[0294] In one embodiment of the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention, the disease,
disorder or condition is responsive to NLRP3 inhibition. As used
herein, the term "NLRP3 inhibition" refers to the complete or
partial reduction in the level of activity of NLRP3 and includes,
for example, the inhibition of active NLRP3 and/or the inhibition
of activation of NLRP3.
[0295] There is evidence for a role of NLRP3-induced IL-1 and IL-18
in the inflammatory responses occurring in connection with, or as a
result of, a multitude of different disorders (Menu et al.,
Clinical and Experimental Immunology, 166: 1-15, 2011; Strowig et
al., Nature, 481:278-286, 2012).
[0296] NLRP3 has been implicated in a number of autoinflammatory
diseases, including Familial Mediterranean fever (FMF), TNF
receptor associated periodic syndrome (TRAPS),
hyperimmunoglobulinemia D and periodic fever syndrome (HIDS),
pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), Sweet's
syndrome, chronic nonbacterial osteomyelitis (CNO), and acne
vulgaris (Cook et al., Eur. J. Immunol., 40: 595-653, 2010). In
particular, NLRP3 mutations have been found to be responsible for a
set of rare autoinflammatory diseases known as CAPS (Ozaki et al.,
J. Inflammation Research, 8:15-27, 2015; Schroder et al., Cell,
140: 821-832, 2010; and Menu et al., Clinical and Experimental
Immunology, 166: 1-15, 2011). CAPS are heritable diseases
characterized by recurrent fever and inflammation and are comprised
of three autoinflammatory disorders that form a clinical continuum.
These diseases, in order of increasing severity, are familial cold
autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and
chronic infantile cutaneous neurological articular syndrome (CINCA;
also called neonatal-onset multisystem inflammatory disease,
NOMID), and all have been shown to result from gain-of-function
mutations in the NLRP3 gene, which leads to increased secretion of
IL-1.beta..
[0297] A number of autoimmune diseases have been shown to involve
NLRP3 including, in particular, multiple sclerosis, type-1 diabetes
(TID), psoriasis, rheumatoid arthritis (RA), Behcet's disease,
Schnitzler syndrome, macrophage activation syndrome (Masters Clin.
Immunol. 2013; Braddock et al., Nat. Rev. Drug Disc. 2004 3: 1-10;
Inoue et al., Immunology 139: 11-18, Coll et al. Nat. Med. 2015
21(3):248-55; and Scott et al. Clin. Exp. Rheumatol 2016 34(1):
88-93), systemic lupus erythematosus (Lu et al. J Immunol. 2017
198(3): 1119-29), and systemic sclerosis (Artlett et al. Arthritis
Rheum. 2011; 63(11): 3563-74). NLRP3 has also been shown to play a
role in a number of lung diseases including chronic obstructive
pulmonary disorder (COPD), asthma (including steroid-resistant
asthma), asbestosis, and silicosis (De Nardo et al., Am. J.
Pathol., 184: 42-54, 2014 and Kim et al. Am J Respir Crit Care Med.
2017 196(3): 283-97). NLRP3 has also been suggested to have a role
in a number of diseases of the central nervous system, including
Parkinson's disease (PD), Alzheimer's disease (AD), dementia,
Huntington's disease, cerebral malaria, brain injury from
pneumococcal meningitis (Walsh et al., Nature Reviews, 15: 84-97,
2014, and Dempsey et al. Brain. Behav. Immun. 2017 61: 306-316),
intracranial aneurysms (Zhang et al. J. Stroke &
Cerebrovascular Dis. 2015 24; 5: 972-979), and traumatic brain
injury (Ismael et al. J Neurotrauma. 2018 Jan. 2). NRLP3 activity
has also been shown to be involved in various metabolic diseases
including type 2 diabetes (T2D), atherosclerosis, obesity, gout,
pseudo-gout, metabolic syndrome (Wen et al., Nature Immunology, 13:
352-357, 2012; Duewell et al., Nature, 464: 1357-1361, 2010;
Strowig et al., Nature, 481: 278-286, 2012), and non-alcoholic
steatohepatitis (Mridha et al. J Hepatol. 2017 66(5): 1037-46). A
role for NLRP3 via IL-1.beta. has also been suggested in
atherosclerosis, myocardial infarction (van Hout et al. Eur. Heart
J. 2017 38(11): 828-36), heart failure (Sano et al. J AM. Coll.
Cardiol. 2018 71(8): 875-66), aortic aneurysm and dissection (Wu et
al. Arterioscler. Thromb. Vasc. Biol. 2017 37(4): 694-706), and
other cardiovascular events (Ridker et al., N Engl J Med., doi:
10.1056/NEJMoa1707914, 2017). Other diseases in which NLRP3 has
been shown to be involved include: ocular diseases such as both wet
and dry age-related macular degeneration (Doyle et al., Nature
Medicine, 18: 791-798, 2012 and Tarallo et al. Cell 2012 149(4):
847-59), diabetic retinopathy (Loukovaara et al. Acta Ophthalmol.
2017; 95(8): 803-808) and optic nerve damage (Puyang et al. Sci
Rep. 2016 Feb. 19; 6:20998); liver diseases including non-alcoholic
steatohepatitis (NASH) (Henao-Meija et al., Nature, 482: 179-185,
2012); inflammatory reactions in the lung and skin (Primiano et al.
J Immunol. 2016 197(6): 2421-33) including contact hypersensitivity
(such as bullous pemphigoid (Fang et al. J Dermatol Sci. 2016;
83(2): 116-23)), atopic dermatitis (Niebuhr et al. Allergy 2014
69(8): 1058-67), Hidradenitis suppurativa (Alikhan et al. 2009 J Am
Acad Dermatol 60(4): 539-61), acne vulgaris (Qin et al. J Invest.
Dermatol. 2014 134(2): 381-88), and sarcoidosis (Jager et al. Am J
Respir Crit Care Med 2015 191: A5816); inflammatory reactions in
the joints (Braddock et al., Nat. Rev. Drug Disc., 3: 1-10, 2004);
amyotrophic lateral sclerosis (Gugliandolo et al. Inflammation 2018
41(1): 93-103); cystic fibrosis (Iannitti et al. Nat. Commun. 2016
7: 10791); stroke (Walsh et al., Nature Reviews, 15: 84-97, 2014);
chronic kidney disease (Granata et al. PLoS One 2015 10(3):
e0122272); and inflammatory bowel diseases including ulcerative
colitis and Crohn's disease (Braddock et al., Nat. Rev. Drug Disc.,
3: 1-10, 2004, Neudecker et al. J Exp. Med. 2017 214(6): 1737-52,
and Lazaridis et al. Dig. Dis. Sci. 2017 62(9): 2348-56). The NLRP3
inflammasome has been found to be activated in response to
oxidative stress, and UVB irradiation (Schroder et al., Science,
327: 296-300, 2010). NLRP3 has also been shown to be involved in
inflammatory hyperalgesia (Dolunay et al., Inflammation, 40:
366-386, 2017).
[0298] The inflammasome, and NLRP3 specifically, has also been
proposed as a target for modulation by various pathogens including
viruses such as DNA viruses (Amsler et al., Future Virol. (2013)
8(4), 357-370).
[0299] NLRP3 has also been implicated in the pathogenesis of many
cancers (Menu et al., Clinical and Experimental Immunology 166:
1-15, 2011; and Masters Clin. Immunol. 2013). For example, several
previous studies have suggested a role for IL-1.beta. in cancer
invasiveness, growth and metastasis, and inhibition of IL-1.beta.
with canakinumab has been shown to reduce the incidence of lung
cancer and total cancer mortality in a randomised, double-blind,
placebo-controlled trial (Ridker et al. Lancet,
S0140-6736(17)32247-X, 2017). Inhibition of the NLRP3 inflammasome
or IL-1.beta. has also been shown to inhibit the proliferation and
migration of lung cancer cells in vitro (Wang et al. Oncol Rep.
2016; 35(4): 2053-64). A role for the NLRP3 inflammasome has been
suggested in myelodysplastic syndromes (Basiorka et al. Blood. 2016
Dec. 22; 128(25):2960-2975) and also in the carcinogenesis of
various other cancers including glioma (Li et al. Am J Cancer Res.
2015; 5(1): 442-449), inflammation-induced tumours (Allen et al. J
Exp Med. 2010; 207(5): 1045-56 and Hu et al. PNAS. 2010; 107(50):
21635-40), multiple myeloma (Li et al. Hematology 2016 21(3):
144-51), and squamous cell carcinoma of the head and neck (Huang et
al. J Exp Clin Cancer Res. 2017 2; 36(1): 116). Activation of the
NLRP3 inflammasome has also been shown to mediate chemoresistance
of tumour cells to 5-Fluorouracil (Feng et al. J Exp Clin Cancer
Res. 2017 21; 36(1): 81), and activation of NLRP3 inflammasome in
peripheral nerve contributes to chemotherapy-induced neuropathic
pain (Jia et al. Mol Pain. 2017; 13: 1-11).
[0300] NLRP3 has also been shown to be required for the efficient
control of viral, bacterial, fungal, and helminth pathogen
infections (Strowig et al., Nature, 481:278-286, 2012).
[0301] Accordingly, examples of diseases, disorders or conditions
which may be responsive to NLRP3 inhibition and which may be
treated or prevented in accordance with the fifth, sixth, seventh,
eighth, ninth or tenth aspect of the present invention include:
[0302] (i) inflammation, including inflammation occurring as a
result of an inflammatory disorder, e.g. an autoinflammatory
disease, inflammation occurring as a symptom of a non-inflammatory
disorder, inflammation occurring as a result of infection, or
inflammation secondary to trauma, injury or autoimmunity;
[0303] (ii) auto-immune diseases such as acute disseminated
encephalitis, Addison's disease, ankylosing spondylitis,
antiphospholipid antibody syndrome (APS), anti-synthetase syndrome,
aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis,
autoimmune oophoritis, autoimmune polyglandular failure, autoimmune
thyroiditis, Coeliac disease, Crohn's disease, type 1 diabetes
(TID), Goodpasture's syndrome, Graves' disease, Guillain-Barre
syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic
purpura, Kawasaki's disease, lupus erythematosus including systemic
lupus erythematosus (SLE), multiple sclerosis (MS) including
primary progressive multiple sclerosis (PPMS), secondary
progressive multiple sclerosis (SPMS) and relapsing remitting
multiple sclerosis (RRMS), myasthenia gravis, opsoclonus myoclonus
syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus,
pernicious anaemia, polyarthritis, primary biliary cirrhosis,
rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic
arthritis or Still's disease, refractory gouty arthritis, Reiter's
syndrome, Sjogren's syndrome, systemic sclerosis a systemic
connective tissue disorder, Takayasu's arteritis, temporal
arteritis, warm autoimmune hemolytic anemia, Wegener's
granulomatosis, alopecia universalis, Behcet's disease, Chagas'
disease, dysautonomia, endometriosis, hidradenitis suppurativa
(HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis,
scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage
activation syndrome, Blau syndrome, vitiligo or vulvodynia;
[0304] (iii) cancer including lung cancer, pancreatic cancer,
gastric cancer, myelodysplastic syndrome, leukaemia including acute
lymphocytic leukaemia (ALL) and acute myeloid leukaemia (AML),
adrenal cancer, anal cancer, basal and squamous cell skin cancer,
bile duct cancer, bladder cancer, bone cancer, brain and spinal
cord tumours, breast cancer, cervical cancer, chronic lymphocytic
leukaemia (CLL), chronic myeloid leukaemia (CML), chronic
myelomonocytic leukaemia (CMML), colorectal cancer, endometrial
cancer, oesophagus cancer, Ewing family of tumours, eye cancer,
gallbladder cancer, gastrointestinal carcinoid tumours,
gastrointestinal stromal tumour (GIST), gestational trophoblastic
disease, glioma, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer,
laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid
tumour, lymphoma including cutaneous T cell lymphoma, malignant
mesothelioma, melanoma skin cancer, Merkel cell skin cancer,
multiple myeloma, nasal cavity and paranasal sinuses cancer,
nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,
non-small cell lung cancer, oral cavity and oropharyngeal cancer,
osteosarcoma, ovarian cancer, penile cancer, pituitary tumours,
prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland
cancer, skin cancer, small cell lung cancer, small intestine
cancer, soft tissue sarcoma, stomach cancer, testicular cancer,
thymus cancer, thyroid cancer including anaplastic thyroid cancer,
uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom
macroglobulinemia, and Wilms tumour;
[0305] (iv) infections including viral infections (e.g. from
influenza virus, human immunodeficiency virus (HIV), alphavirus
(such as Chikungunya and Ross River virus), flaviviruses (such as
Dengue virus and Zika virus), herpes viruses (such as Epstein Barr
Virus, cytomegalovirus, Varicella-zoster virus, and KSHV),
poxviruses (such as vaccinia virus (Modified vaccinia virus Ankara)
and Myxoma virus), adenoviruses (such as Adenovirus 5), or
papillomavirus), bacterial infections (e.g. from Staphylococcus
aureus, Helicobacter pylori, Bacillus anthracis, Bordatella
pertussis, Burkholderia pseudomallei, Corynebacterium diptheriae,
Clostridium tetani, Clostridium botulinum, Streptococcus
pneumoniae, Streptococcus pyogenes, Listeria monocytogenes,
Hemophilus influenzae, Pasteurella multicida, Shigella dysenteriae,
Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma
pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria
gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila,
Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium
acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae,
Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi or
Yersinia pestis), fungal infections (e.g. from Candida or
Aspergillus species), protozoan infections (e.g. from Plasmodium,
Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes), helminth
infections (e.g. from schistosoma, roundworms, tapeworms or flukes)
and prion infections;
[0306] (v) central nervous system diseases such as Parkinson's
disease, Alzheimer's disease, dementia, motor neuron disease,
Huntington's disease, cerebral malaria, brain injury from
pneumococcal meningitis, intracranial aneurysms, traumatic brain
injury, and amyotrophic lateral sclerosis;
[0307] (vi) metabolic diseases such as type 2 diabetes (T2D),
atherosclerosis, obesity, gout, and pseudo-gout;
[0308] (vii) cardiovascular diseases such as hypertension,
ischaemia, reperfusion injury including post-MI ischemic
reperfusion injury, stroke including ischemic stroke, transient
ischemic attack, myocardial infarction including recurrent
myocardial infarction, heart failure including congestive heart
failure and heart failure with preserved ejection fraction,
embolism, aneurysms including abdominal aortic aneurysm, and
pericarditis including Dressler's syndrome;
[0309] (viii) respiratory diseases including chronic obstructive
pulmonary disorder (COPD), asthma such as allergic asthma and
steroid-resistant asthma, asbestosis, silicosis, nanoparticle
induced inflammation, cystic fibrosis and idiopathic pulmonary
fibrosis;
[0310] (ix) liver diseases including non-alcoholic fatty liver
disease (NAFLD) and non-alcoholic steatohepatitis (NASH) including
advanced fibrosis stages F3 and F4, alcoholic fatty liver disease
(AFLD), and alcoholic steatohepatitis (ASH);
[0311] (x) renal diseases including chronic kidney disease, oxalate
nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic
nephropathy;
[0312] (xi) ocular diseases including those of the ocular
epithelium, age-related macular degeneration (AMD) (dry and wet),
uveitis, corneal infection, diabetic retinopathy, optic nerve
damage, dry eye, and glaucoma;
[0313] (xii) skin diseases including dermatitis such as contact
dermatitis and atopic dermatitis, contact hypersensitivity,
sunburn, skin lesions, hidradenitis suppurativa (HS), other
cyst-causing skin diseases, and acne conglobata;
[0314] (xiii) lymphatic conditions such as lymphangitis and
Castleman's disease;
[0315] (xiv) psychological disorders such as depression and
psychological stress;
[0316] (xv) graft versus host disease;
[0317] (xvi) allodynia including mechanical allodynia; and
[0318] (xvii) any disease where an individual has been determined
to carry a germline or somatic non-silent mutation in NLRP3.
[0319] In one embodiment, the disease, disorder or condition is
selected from:
[0320] (i) cancer;
[0321] (ii) an infection;
[0322] (iii) a central nervous system disease;
[0323] (iv) a cardiovascular disease;
[0324] (v) a liver disease;
[0325] (vi) an ocular diseases; or
[0326] (vii) a skin disease.
[0327] More typically, the disease, disorder or condition is
selected from:
[0328] (i) cancer;
[0329] (ii) an infection;
[0330] (iii) a central nervous system disease; or
[0331] (iv) a cardiovascular disease.
[0332] In one embodiment, the disease, disorder or condition is
selected from:
[0333] (i) acne conglobata;
[0334] (ii) atopic dermatitis;
[0335] (iii) Alzheimer's disease;
[0336] (iv) amyotrophic lateral sclerosis;
[0337] (v) age-related macular degeneration (AMD);
[0338] (vi) anaplastic thyroid cancer;
[0339] (vii) cryopyrin-associated periodic syndromes (CAPS);
[0340] (viii) contact dermatitis;
[0341] (ix) cystic fibrosis;
[0342] (x) congestive heart failure;
[0343] (xi) chronic kidney disease;
[0344] (xii) Crohn's disease;
[0345] (xiii) familial cold autoinflammatory syndrome (FCAS);
[0346] (xiv) Huntington's disease;
[0347] (xv) heart failure;
[0348] (xvi) heart failure with preserved ejection fraction;
[0349] (xvii) ischemic reperfusion injury;
[0350] (xviii) juvenile idiopathic arthritis;
[0351] (xix) myocardial infarction;
[0352] (xx) macrophage activation syndrome;
[0353] (xxi) myelodysplastic syndrome;
[0354] (xxii) multiple myeloma;
[0355] (xxiii) motor neuron disease;
[0356] (xxiv) multiple sclerosis;
[0357] (xxv) Muckle-Wells syndrome;
[0358] (xxvi) non-alcoholic steatohepatitis (NASH);
[0359] (xxvii) neonatal-onset multisystem inflammatory disease
(NOMID);
[0360] (xxviii) Parkinson's disease;
[0361] (xxix) systemic juvenile idiopathic arthritis;
[0362] (xxx) systemic lupus erythematosus;
[0363] (xxxi) traumatic brain injury;
[0364] (xxxii) transient ischemic attack; and
[0365] (xxxiii) ulcerative colitis.
[0366] In a further typical embodiment of the invention, the
disease, disorder or condition is inflammation. Examples of
inflammation that may be treated or prevented in accordance with
the fifth, sixth, seventh, eighth, ninth or tenth aspect of the
present invention include inflammatory responses occurring in
connection with, or as a result of:
[0367] (i) a skin condition such as contact hypersensitivity,
bullous pemphigoid, sunburn, psoriasis, atopical dermatitis,
contact dermatitis, allergic contact dermatitis, seborrhoetic
dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis
bullosa, urticaria, erythemas, or alopecia;
[0368] (ii) a joint condition such as osteoarthritis, systemic
juvenile idiopathic arthritis, adult-onset Still's disease,
relapsing polychondritis, rheumatoid arthritis, juvenile chronic
arthritis, gout, or a seronegative spondyloarthropathy (e.g.
ankylosing spondylitis, psoriatic arthritis or Reiter's
disease);
[0369] (iii) a muscular condition such as polymyositis or
myasthenia gravis;
[0370] (iv) a gastrointestinal tract condition such as inflammatory
bowel disease (including Crohn's disease and ulcerative colitis),
gastric ulcer, coeliac disease, proctitis, pancreatitis,
eosinopilic gastro-enteritis, mastocytosis, antiphospholipid
syndrome, or a food-related allergy which may have effects remote
from the gut (e.g., migraine, rhinitis or eczema);
[0371] (v) a respiratory system condition such as chronic
obstructive pulmonary disease (COPD), asthma (including bronchial,
allergic, intrinsic, extrinsic or dust asthma, and particularly
chronic or inveterate asthma, such as late asthma and airways
hyper-responsiveness), bronchitis, rhinitis (including acute
rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis,
rhinitis caseosa, hypertrophic rhinitis, rhinitis pumlenta,
rhinitis sicca, rhinitis medicamentosa, membranous rhinitis,
seasonal rhinitis e.g. hay fever, and vasomotor rhinitis),
sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis,
farmer's lung, silicosis, asbestosis, adult respiratory distress
syndrome, hypersensitivity pneumonitis, or idiopathic interstitial
pneumonia;
[0372] (vi) a vascular condition such as atherosclerosis, Behcet's
disease, vasculitides, or wegener's granulomatosis;
[0373] (vii) an autoimmune condition such as systemic lupus
erythematosus, Sjogren's syndrome, systemic sclerosis, Hashimoto's
thyroiditis, type I diabetes, idiopathic thrombocytopenia purpura,
or Graves disease;
[0374] (viii) an ocular condition such as uveitis, allergic
conjunctivitis, or vernal conjunctivitis;
[0375] (ix) a nervous condition such as multiple sclerosis or
encephalomyelitis;
[0376] (x) an infection or infection-related condition, such as
Acquired Immunodeficiency Syndrome (AIDS), acute or chronic
bacterial infection, acute or chronic parasitic infection, acute or
chronic viral infection, acute or chronic fungal infection,
meningitis, hepatitis (A, B or C, or other viral hepatitis),
peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic
fever, leishmaniasis, streptococcal myositis, Mycobacterium
tuberculosis, Mycobacterium avium intracellulare, Pneumocystis
carinii pneumonia, orchitis/epidydimitis, legionella, Lyme disease,
influenza A, epstein-barr virus, viral encephalitis/aseptic
meningitis, or pelvic inflammatory disease;
[0377] (xi) a renal condition such as mesangial proliferative
glomerulonephritis, nephrotic syndrome, nephritis, glomerular
nephritis, acute renal failure, uremia, or nephritic syndrome;
[0378] (xii) a lymphatic condition such as Castleman's disease;
[0379] (xiii) a condition of, or involving, the immune system, such
as hyper IgE syndrome, lepromatous leprosy, familial hemophagocytic
lymphohistiocytosis, or graft versus host disease;
[0380] (xiv) a hepatic condition such as chronic active hepatitis,
non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis,
non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver
disease (AFLD), alcoholic steatohepatitis (ASH) or primary biliary
cirrhosis;
[0381] (xv) a cancer, including those cancers listed above;
[0382] (xvi) a burn, wound, trauma, haemorrhage or stroke;
[0383] (xvii) radiation exposure; and/or
[0384] (xviii) obesity; and/or
[0385] (xix) pain such as inflammatory hyperalgesia.
[0386] In one embodiment of the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention, the disease,
disorder or condition is an autoinflammatory disease such as
cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells
syndrome (MWS), familial cold autoinflammatory syndrome (FCAS),
familial Mediterranean fever (FMF), neonatal onset multisystem
inflammatory disease (NOMID), Tumour Necrosis Factor (TNF)
Receptor-Associated Periodic Syndrome (TRAPS),
hyperimmunoglobulinemia D and periodic fever syndrome (HIDS),
deficiency of interleukin 1 receptor antagonist (DIRA), Majeed
syndrome, pyogenic arthritis, pyoderma gangrenosum and acne
syndrome (PAPA), adult-onset Still's disease (AOSD),
haploinsufficiency of A20 (HA20), pediatric granulomatous arthritis
(PGA), PLCG2-associated antibody deficiency and immune
dysregulation (PLAID), PLCG2-associated autoinflammatory, antibody
deficiency and immune dysregulation (APLAID), or sideroblastic
anaemia with B-cell immunodeficiency, periodic fevers and
developmental delay (SIFD).
[0387] Examples of diseases, disorders or conditions which may be
responsive to NLRP3 inhibition and which may be treated or
prevented in accordance with the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention are listed above.
Some of these diseases, disorders or conditions are substantially
or entirely mediated by NLRP3 inflammasome activity, and
NLRP3-induced IL-13 and/or IL-18. As a result, such diseases,
disorders or conditions may be particularly responsive to NLRP3
inhibition and may be particularly suitable for treatment or
prevention in accordance with the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention. Examples of such
diseases, disorders or conditions include cryopyrin-associated
periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial
cold autoinflammatory syndrome (FCAS), neonatal onset multisystem
inflammatory disease (NOMID), familial Mediterranean fever (FMF),
pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA),
hyperimmunoglobulinemia D and periodic fever syndrome (HIDS),
Tumour Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome
(TRAPS), systemic juvenile idiopathic arthritis, adult-onset
Still's disease (AOSD), relapsing polychondritis, Schnitzler's
syndrome, Sweet's syndrome, Behcet's disease, anti-synthetase
syndrome, deficiency of interleukin 1 receptor antagonist (DIRA),
and haploinsufficiency of A20 (HA20).
[0388] Moreover, some of the diseases, disorders or conditions
mentioned above arise due to mutations in NLRP3, in particular,
resulting in increased NLRP3 activity. As a result, such diseases,
disorders or conditions may be particularly responsive to NLRP3
inhibition and may be particularly suitable for treatment or
prevention in accordance with the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention. Examples of such
diseases, disorders or conditions include cryopyrin-associated
periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial
cold autoinflammatory syndrome (FCAS), and neonatal onset
multisystem inflammatory disease (NOMID).
[0389] In one embodiment of the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention, the disease,
disorder or condition is not a disease or disorder mediated by
NF.kappa.B. In one embodiment of the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention, the disease,
disorder or condition is not rheumatoid arthritis, osteoarthritis,
an autoimmune disease, psoriasis, asthma, a cardiovascular disease,
an acute coronary syndrome, atherosclerosis, myocardial infarction,
unstable angina, congestive heart failure, Alzheimer's disease,
multiple sclerosis, cancer, type II diabetes, metabolic syndrome X,
inflammatory bowel disease, systemic lupus erythematosus, Grave's
disease, myasthenia gravis, insulin resistance, autoimmune
hemolytic anemia, scleroderma with anticollagen antibodies,
pernicious anemia, or diabetes mellitus. In one embodiment of the
fifth, sixth, seventh, eighth, ninth or tenth aspect of the present
invention, the disease, disorder or condition is not inflammatory
bowel disease. In one embodiment of the fifth, sixth, seventh,
eighth, ninth or tenth aspect of the present invention, the
disease, disorder or condition is not atherosclerosis. In one
embodiment of the fifth, sixth, seventh, eighth, ninth or tenth
aspect of the present invention, the disease, disorder or condition
is not a disease susceptible to treatment with an inhibitor of
acyl-CoA. In one embodiment of the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention, the disease,
disorder or condition is not HCV infection.
[0390] In one embodiment of the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention, the treatment or
prevention comprises topically administering a compound of the
first or second aspect, or a pharmaceutically acceptable salt,
solvate or prodrug of the third aspect, or a pharmaceutical
composition of the fourth aspect. For example, the disease,
disorder or condition may be a skin disease or condition, wherein
the treatment or prevention comprises topically administering a
compound of the first or second aspect, or a pharmaceutically
acceptable salt, solvate or prodrug of the third aspect, or a
pharmaceutical composition of the fourth aspect to the skin.
Alternatively, the disease, disorder or condition may be an ocular
disease or condition, wherein the treatment or prevention comprises
topically administering a compound of the first or second aspect,
or a pharmaceutically acceptable salt, solvate or prodrug of the
third aspect, or a pharmaceutical composition of the fourth aspect
to the eye.
[0391] In one embodiment, where the treatment or prevention
comprises topically administering a compound of the first or second
aspect, or a pharmaceutically acceptable salt, solvate or prodrug
of the third aspect, or a pharmaceutical composition of the fourth
aspect of the invention, one or more further active agents may be
co-administered. The one or more further active agents may also be
topically administered, or may be administered via a non-topical
route. Typically, the one or more further active agents are also
topically administered. For example, where the pharmaceutical
composition of the fourth aspect of the invention is a topical
pharmaceutical composition, the pharmaceutical composition may
further comprise one or more further active agents.
[0392] An eleventh aspect of the invention provides a method of
inhibiting NLRP3, the method comprising the use of a compound of
the first or second aspect of the invention, or a pharmaceutically
acceptable salt, solvate or prodrug of the third aspect of the
invention, or a pharmaceutical composition of the fourth aspect of
the invention, to inhibit NLRP3.
[0393] In one embodiment of the eleventh aspect of the present
invention, the method comprises the use of a compound of the first
or second aspect of the invention, or a pharmaceutically acceptable
salt, solvate or prodrug of the third aspect of the invention, or a
pharmaceutical composition of the fourth aspect of the invention,
in combination with one or more further active agents.
[0394] In one embodiment of the eleventh aspect of the present
invention, the method is performed ex vivo or in vitro, for example
in order to analyse the effect on cells of NLRP3 inhibition.
[0395] In another embodiment of the eleventh aspect of the present
invention, the method is performed in vivo. For example, the method
may comprise the step of administering an effective amount of a
compound of the first or second aspect, or a pharmaceutically
acceptable salt, solvate or prodrug of the third aspect, or a
pharmaceutical composition of the fourth aspect, to thereby inhibit
NLRP3. In one embodiment, the method further comprises the step of
co-administering an effective amount of one or more further active
agents. Typically the administration is to a subject in need
thereof.
[0396] Alternately, the method of the eleventh aspect of the
invention may be a method of inhibiting NLRP3 in a non-human animal
subject, the method comprising the steps of administering the
compound, salt, solvate, prodrug or pharmaceutical composition to
the non-human animal subject and optionally subsequently mutilating
or sacrificing the non-human animal subject. Typically such a
method further comprises the step of analysing one or more tissue
or fluid samples from the optionally mutilated or sacrificed
non-human animal subject. In one embodiment, the method further
comprises the step of co-administering an effective amount of one
or more further active agents.
[0397] A twelfth aspect of the invention provides a compound of the
first or second aspect of the invention, or a pharmaceutically
acceptable salt, solvate or prodrug of the third aspect of the
invention, or a pharmaceutical composition of the fourth aspect of
the invention, for use in the inhibition of NLRP3. Typically the
use comprises the administration of the compound, salt, solvate,
prodrug or pharmaceutical composition to a subject. In one
embodiment, the compound, salt, solvate, prodrug or pharmaceutical
composition is co-administered with one or more further active
agents.
[0398] A thirteenth aspect of the invention provides the use of a
compound of the first or second aspect of the invention, or a
pharmaceutically effective salt, solvate or prodrug of the third
aspect of the invention, in the manufacture of a medicament for the
inhibition of NLRP3. Typically the inhibition comprises the
administration of the compound, salt, solvate, prodrug or
medicament to a subject. In one embodiment, the compound, salt,
solvate, prodrug or medicament is co-administered with one or more
further active agents.
[0399] In any embodiment of any of the fifth to thirteenth aspects
of the present invention that comprises the use or
co-administration of one or more further active agents, the one or
more further active agents may comprise for example one, two or
three different further active agents.
[0400] The one or more further active agents may be used or
administered prior to, simultaneously with, sequentially with or
subsequent to each other and/or to the compound of the first or
second aspect of the invention, the pharmaceutically acceptable
salt, solvate or prodrug of the third aspect of the invention, or
the pharmaceutical composition of the fourth aspect of the
invention. Where the one or more further active agents are
administered simultaneously with the compound of the first or
second aspect of the invention, or the pharmaceutically acceptable
salt, solvate or prodrug of the third aspect of the invention, a
pharmaceutical composition of the fourth aspect of the invention
may be administered wherein the pharmaceutical composition
additionally comprises the one or more further active agents.
[0401] In one embodiment of any of the fifth to thirteenth aspects
of the present invention that comprises the use or
co-administration of one or more further active agents, the one or
more further active agents are selected from:
[0402] (i) chemotherapeutic agents;
[0403] (ii) antibodies;
[0404] (iii) alkylating agents;
[0405] (iv) anti-metabolites;
[0406] (v) anti-angiogenic agents;
[0407] (vi) plant alkaloids and/or terpenoids;
[0408] (vii) topoisomerase inhibitors;
[0409] (viii) mTOR inhibitors;
[0410] (ix) stilbenoids;
[0411] (x) STING agonists;
[0412] (xi) cancer vaccines;
[0413] (xii) immunomodulatory agents;
[0414] (xiii) antibiotics;
[0415] (xiv) anti-fungal agents;
[0416] (xv) anti-helminthic agents; and/or
[0417] (xvi) other active agents.
[0418] It will be appreciated that these general embodiments
defined according to broad categories of active agents are not
mutually exclusive. In this regard any particular active agent may
be categorized according to more than one of the above general
embodiments. A non-limiting example is urelumab which is an
antibody that is an immunomodulatory agent for the treatment of
cancer.
[0419] In some embodiments, the one or more chemotherapeutic agents
are selected from abiraterone acetate, altretamine, amsacrine,
anhydrovinblastine, auristatin, azathioprine, adriamycin,
bexarotene, bicalutamide, BMS 184476, bleomycin,
N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butyla-
mide, cisplatin, carboplatin, carboplatin cyclophosphamide,
chlorambucil, cachectin, cemadotin, cyclophosphamide, carmustine,
cryptophycin, cytarabine, docetaxel, doxetaxel, doxorubicin,
dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine,
dolastatin, etoposide, etoposide phosphate, enzalutamide (MDV3100),
5-fluorouracil, fludarabine, flutamide, gemcitabine, hydroxyurea
and hydroxyureataxanes, idarubicin, ifosfamide, irinotecan,
leucovorin, lonidamine, lomustine (CCNU), larotaxel (RPR109881),
mechlorethamine, mercaptopurine, methotrexate, mitomycin C,
mitoxantrone, melphalan, mivobulin,
3',4'-didehydro-4'-deoxy-8'-norvin-caleukoblastine, nilutamide,
oxaliplatin, onapristone, prednimustine, procarbazine, paclitaxel,
platinum-containing anti-cancer agents,
2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene
sulphonamide, prednimustine, procarbazine, rhizoxin, sertenef,
streptozocin, stramustine phosphate, tretinoin, tasonermin, taxol,
topotecan, tamoxifen, teniposide, taxane, tegafur/uracil,
vincristine, vinblastine, vinorelbine, vindesine, vindesine
sulfate, and/or vinflunine.
[0420] Alternatively or in addition, the one or more
chemotherapeutic agents may be selected from CD59 complement
fragment, fibronectin fragment, gro-beta (CXCL2), heparinases,
heparin hexasaccharide fragment, human chorionic gonadotropin
(hCG), interferon alpha, interferon beta, interferon gamma,
interferon inducible protein (IP-10), interleukin-12, kringle 5
(plasminogen fragment), metalloproteinase inhibitors (TIMPs),
2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen
activator inhibitor, platelet factor-4 (PF4), prolactin 16 kD
fragment, proliferin-related protein (PRP), various retinoids,
tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth
factor-beta (TGF-.beta.), vasculostatin, vasostatin (calreticulin
fragment), and/or cytokines (including interleukins, such as
interleukin-2 (IL-2), or IL-10).
[0421] In some embodiments, the one or more antibodies may comprise
one or more monoclonal antibodies. In some embodiments, the one or
more antibodies are selected from abciximab, adalimumab,
alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab,
bretuximab vedotin, canakinumab, cetuximab, ceertolizumab pegol,
daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab,
golimumab, ibritumomab tiuxetan, infliximab, ipilimumab,
muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab,
panitumuab, ranibizumab, rituximab, tocilizumab, tositumomab,
and/or trastuzumab.
[0422] In some embodiments, the one or more alkylating agents may
comprise an agent capable of alkylating nucleophilic functional
groups under conditions present in cells, including, for example,
cancer cells. In some embodiments, the one or more alkylating
agents are selected from cisplatin, carboplatin, mechlorethamine,
cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin. In
some embodiments, the alkylating agent may function by impairing
cell function by forming covalent bonds with amino, carboxyl,
sulfhydryl, and/or phosphate groups in biologically important
molecules. In some embodiments, the alkylating agent may function
by modifying a cell's DNA.
[0423] In some embodiments, the one or more anti-metabolites may
comprise an agent capable of affecting or preventing RNA or DNA
synthesis. In some embodiments, the one or more anti-metabolites
are selected from azathioprine and/or mercaptopurine.
[0424] In some embodiments, the one or more anti-angiogenic agents
are selected from endostatin, angiogenin inhibitors, angiostatin,
angioarrestin, angiostatin (plasminogen fragment),
basement-membrane collagen-derived anti-angiogenic factors
(tumstatin, canstatin, or arrestin), anti-angiogenic antithrombin
III, and/or cartilage-derived inhibitor (CDI).
[0425] In some embodiments, the one or more plant alkaloids and/or
terpenoids may prevent microtubule function. In some embodiments,
the one or more plant alkaloids and/or terpenoids are selected from
a vinca alkaloid, a podophyllotoxin and/or a taxane. In some
embodiments, the one or more vinca alkaloids may be derived from
the Madagascar periwinkle, Catharanthus roseus (formerly known as
Vinca rosea), and may be selected from vincristine, vinblastine,
vinorelbine and/or vindesine. In some embodiments, the one or more
taxanes are selected from taxol, paclitaxel, docetaxel and/or
ortataxel. In some embodiments, the one or more podophyllotoxins
are selected from an etoposide and/or teniposide.
[0426] In some embodiments, the one or more topoisomerase
inhibitors are selected from a type I topoisomerase inhibitor
and/or a type II topoisomerase inhibitor, and may interfere with
transcription and/or replication of DNA by interfering with DNA
supercoiling. In some embodiments, the one or more type I
topoisomerase inhibitors may comprise a camptothecin, which may be
selected from exatecan, irinotecan, lurtotecan, topotecan, BNP
1350, CKD 602, DB 67 (AR67) and/or ST 1481. In some embodiments,
the one or more type II topoisomerase inhibitors may comprise an
epipodophyllotoxin, which may be selected from an amsacrine,
etoposid, etoposide phosphate and/or teniposide.
[0427] In some embodiments, the one or more mTOR (mammalian target
of rapamycin, also known as the mechanistic target of rapamycin)
inhibitors are selected from rapamycin, everolimus, temsirolimus
and/or deforolimus.
[0428] In some embodiments, the one or more stilbenoids are
selected from resveratrol, piceatannol, pinosylvin, pterostilbene,
alpha-viniferin, ampelopsin A, ampelopsin E, diptoindonesin C,
diptoindonesin F, epsilon-vinferin, flexuosol A, gnetin H,
hemsleyanol D, hopeaphenol, trans-diptoindonesin B, astringin,
piceid and/or diptoindonesin A.
[0429] In some embodiments, the one or more STING (Stimulator of
interferon genes, also known as transmembrane protein (TMEM) 173)
agonists may comprise cyclic di-nucleotides, such as cAMP, cGMP,
and cGAMP, and/or modified cyclic di-nucleotides that may include
one or more of the following modification features: 2'-O/3'-O
linkage, phosphorothioate linkage, adenine and/or guanine analogue,
and/or 2'-OH modification (e.g. protection of the 2'-OH with a
methyl group or replacement of the 2'-OH by --F or --N.sub.3).
[0430] In some embodiments, the one or more cancer vaccines are
selected from an HPV vaccine, a hepatitis B vaccine, Oncophage,
and/or Provenge.
[0431] In some embodiments, the one or more immunomodulatory agents
may comprise an immune checkpoint inhibitor. The immune checkpoint
inhibitor may target an immune checkpoint receptor, or combination
of receptors comprising, for example, CTLA-4, PD-1, PD-L1, PD-L2, T
cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9,
phosphatidylserine, lymphocyte activation gene 3 protein (LAG3),
MHC class I, MHC class II, 4-1BB, 4-1BBL, OX40, OX40L, GITR, GITRL,
CD27, CD70, TNFRSF25, TLIA, CD40, CD40L, HVEM, LIGHT, BTLA, CDG60,
CD80, CD244, CD48, ICOS, ICOSL, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2,
TMIGD2, a butyrophilin (including BTNL2), a Siglec family member,
TIGIT, PVR, a killer-cell immunoglobulin-like receptor, an ILT, a
leukocyte immunoglobulin-like receptor, NKG2D, NKG2A, MICA, MICB,
CD28, CD86, SIRPA, CD47, VEGF, neuropilin, CD30, CD39, CD73, CXCR4,
and/or CXCL12.
[0432] In some embodiments, the immune checkpoint inhibitor is
selected from urelumab, PF-05082566, MEDI6469, TRX518, varlilumab,
CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab
(formerly MPDL3280A) (PD-L1), MEDI4736 (PD-L1), avelumab (PD-L1),
PDRool (PD1), BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab,
INCB0243600, galunisertib, ulocuplumab, BKT140, bavituximab,
CC-90002, bevacizumab, and/or MNRP1685A.
[0433] In some embodiments, the one or more antibiotics are
selected from amikacin, gentamicin, kanamycin, neomycin,
netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin,
geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem,
doripenem, imipenem, cilastatin, meropenem, cefadroxil, cefazolin,
cefalotin, cefalothin, cefalexin, cefaclor, cefamandole, cefoxitin,
cefprozil, cefuroxime, cefixime, cefdinir, cefditoren,
cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten,
ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil,
ceftobiprole, teicoplanin, vancomycin, telavancin, dalbavancin,
oritavancin, clindamycin, lincomycin, daptomycin, azithromycin,
clarithromycin, dirithromycin, erythromycin, roxithromycin,
troleandomycin, telithromycin, spiramycin, aztreonam, furazolidone,
nitrofurantoin, linezolid, posizolid, radezolid, torezolid,
amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin,
dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin,
oxacillin, penicillin G, penicillin V, piperacillin, temocillin,
ticarcillin, calvulanate, ampicillin, subbactam, tazobactam,
ticarcillin, clavulanate, bacitracin, colistin, polymyxin B,
ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin,
lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin,
trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide,
sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine,
sulfamethoxazole, sulfanamide, sulfasalazine, sulfisoxazole,
trimethoprim-sulfamethoxazole, sulfonamideochrysoidine,
demeclocycline, minocycline, oytetracycline, tetracycline,
clofazimine, dapsone, dapreomycin, cycloserine, ethambutol,
ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin,
rifapentine, streptomycin, arsphenamine, chloramphenicol,
fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin,
quinupristin, dalopristin, thiamphenicol, tigecycyline, tinidazole,
trimethoprim, and/or teixobactin.
[0434] In some embodiments, the one or more antibiotics may
comprise one or more cytotoxic antibiotics. In some embodiments,
the one or more cytotoxic antibiotics are selected from an
actinomycin, an anthracenedione, an anthracycline, thalidomide,
dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and/or
chlofazimine. In some embodiments, the one or more actinomycins are
selected from actinomycin D, bacitracin, colistin (polymyxin E)
and/or polymyxin B. In some embodiments, the one or more
antracenediones are selected from mitoxantrone and/or pixantrone.
In some embodiments, the one or more anthracyclines are selected
from bleomycin, doxorubicin (Adriamycin), daunorubicin
(daunomycin), epirubicin, idarubicin, mitomycin, plicamycin and/or
valrubicin.
[0435] In some embodiments, the one or more anti-fungal agents are
selected from bifonazole, butoconazole, clotrimazole, econazole,
ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole,
sertaconazole, sulconazole, tioconazole, albaconazole,
efinaconazole, epoziconazole, fluconazole, isavuconazole,
itraconazole, posaconazole, propiconazole, ravusconazole,
terconazole, voriconazole, abafungin, amorolfin, butenafine,
naftifine, terbinafine, anidulafungin, caspofungin, micafungin,
benzoic acid, ciclopirox, flucytosine, 5-fluorocytosine,
griseofulvin, haloprogin, tolnaflate, undecylenic acid, and/or
balsam of Peru.
[0436] In some embodiments, the one or more anti-helminthic agents
are selected from benzimidazoles (including albendazole,
mebendazole, thiabendazole, fenbendazole, triclabendazole, and
flubendazole), abamectin, diethylcarbamazine, ivermectin, suramin,
pyrantel pamoate, levamisole, salicylanilides (including
niclosamide and oxyclozanide), and/or nitazoxanide.
[0437] In some embodiments, other active agents are selected from
growth inhibitory agents, anti-inflammatory agents (including
nonsteroidal anti-inflammatory agents), anti-psoriatic agents
(including anthralin and its derivatives), vitamins and
vitamin-derivatives (including retinoinds, and VDR receptor
ligands), corticosteroids, ion channel blockers (including
potassium channel blockers), immune system regulators (including
cyclosporin, FK 506, and glucocorticoids), lutenizing hormone
releasing hormone agonists (such as leuprolidine, goserelin,
triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide),
and/or hormones (including estrogen).
[0438] Unless stated otherwise, in any of the fifth to thirteenth
aspects of the invention, the subject may be any human or other
animal. Typically, the subject is a mammal, more typically a human
or a domesticated mammal such as a cow, pig, lamb, sheep, goat,
horse, cat, dog, rabbit, mouse etc. Most typically, the subject is
a human.
[0439] Any of the medicaments employed in the present invention can
be administered by oral, parenteral (including intravenous,
subcutaneous, intramuscular, intradermal, intratracheal,
intraperitoneal, intraarticular, intracranial and epidural), airway
(aerosol), rectal, vaginal, ocular or topical (including
transdermal, buccal, mucosal, sublingual and topical ocular)
administration.
[0440] Typically, the mode of administration selected is that most
appropriate to the disorder, disease or condition to be treated or
prevented. Where one or more further active agents are
administered, the mode of administration may be the same as or
different to the mode of administration of the compound, salt,
solvate, prodrug or pharmaceutical composition of the
invention.
[0441] For oral administration, the compounds, salts, solvates or
prodrugs of the present invention will generally be provided in the
form of tablets, capsules, hard or soft gelatine capsules, caplets,
troches or lozenges, as a powder or granules, or as an aqueous
solution, suspension or dispersion.
[0442] Tablets for oral use may include the active ingredient mixed
with pharmaceutically acceptable excipients such as inert diluents,
disintegrating agents, binding agents, lubricating agents,
sweetening agents, flavouring agents, colouring agents and
preservatives. Suitable inert diluents include sodium and calcium
carbonate, sodium and calcium phosphate, and lactose. Corn starch
and alginic acid are suitable disintegrating agents. Binding agents
may include starch and gelatine. The lubricating agent, if present,
may be magnesium stearate, stearic acid or talc. If desired, the
tablets may be coated with a material, such as glyceryl
monostearate or glyceryl distearate, to delay absorption in the
gastrointestinal tract. Tablets may also be effervescent and/or
dissolving tablets.
[0443] Capsules for oral use include hard gelatine capsules in
which the active ingredient is mixed with a solid diluent, and soft
gelatine capsules wherein the active ingredient is mixed with water
or an oil such as peanut oil, liquid paraffin or olive oil.
[0444] Powders or granules for oral use may be provided in sachets
or tubs. Aqueous solutions, suspensions or dispersions may be
prepared by the addition of water to powders, granules or
tablets.
[0445] Any form suitable for oral administration may optionally
include sweetening agents such as sugar, flavouring agents,
colouring agents and/or preservatives.
[0446] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising, for example, cocoa
butter or a salicylate.
[0447] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0448] For parenteral use, the compounds, salts, solvates or
prodrugs of the present invention will generally be provided in a
sterile aqueous solution or suspension, buffered to an appropriate
pH and isotonicity. Suitable aqueous vehicles include Ringer's
solution and isotonic sodium chloride or glucose. Aqueous
suspensions according to the invention may include suspending
agents such as cellulose derivatives, sodium alginate,
polyvinylpyrrolidone and gum tragacanth, and a wetting agent such
as lecithin. Suitable preservatives for aqueous suspensions include
ethyl and n-propyl p-hydroxybenzoate. The compounds of the
invention may also be presented as liposome formulations.
[0449] For ocular administration, the compounds, salts, solvates or
prodrugs of the invention will generally be provided in a form
suitable for topical administration, e.g. as eye drops. Suitable
forms may include ophthalmic solutions, gel-forming solutions,
sterile powders for reconstitution, ophthalmic suspensions,
ophthalmic ointments, ophthalmic emulsions, ophthalmic gels and
ocular inserts. Alternatively, the compounds, salts, solvates or
prodrugs of the invention may be provided in a form suitable for
other types of ocular administration, for example as intraocular
preparations (including as irrigating solutions, as intraocular,
intravitreal or juxtascleral injection formulations, or as
intravitreal implants), as packs or corneal shields, as
intracameral, subconjunctival or retrobulbar injection
formulations, or as iontophoresis formulations.
[0450] For transdermal and other topical administration, the
compounds, salts, solvates or prodrugs of the invention will
generally be provided in the form of ointments, cataplasms
(poultices), pastes, powders, dressings, creams, plasters or
patches.
[0451] Suitable suspensions and solutions can be used in inhalers
for airway (aerosol) administration.
[0452] The dose of the compounds, salts, solvates or prodrugs of
the present invention will, of course, vary with the disorder,
disease or condition to be treated or prevented. In general, a
suitable dose will be in the range of 0.01 to 500 mg per kilogram
body weight of the recipient per day. The desired dose may be
presented at an appropriate interval such as once every other day,
once a day, twice a day, three times a day or four times a day. The
desired dose may be administered in unit dosage form, for example,
containing 1 mg to 50 g of active ingredient per unit dosage
form.
[0453] For the avoidance of doubt, insofar as is practicable any
embodiment of a given aspect of the present invention may occur in
combination with any other embodiment of the same aspect of the
present invention. In addition, insofar as is practicable it is to
be understood that any preferred, typical or optional embodiment of
any aspect of the present invention should also be considered as a
preferred, typical or optional embodiment of any other aspect of
the present invention.
EXAMPLES--COMPOUND SYNTHESIS
[0454] All solvents, reagents and compounds were purchased and used
without further purification unless stated otherwise.
Abbreviations
[0455] 2-MeTHF 2-methyltetrahydrofuran [0456] Ac.sub.2O acetic
anhydride [0457] AcOH acetic acid [0458] aq aqueous [0459] Boc
tert-butyloxycarbonyl [0460] br broad [0461] Cbz carboxybenzyl
[0462] CDI 1,1-carbonyl-diimidazole [0463] cone concentrated [0464]
d doublet [0465] DABCO 1,4-diazabicyclo [2.2.2]octane [0466] DCE
1,2-dichloroethane, also called ethylene dichloride [0467] DCM
dichloromethane [0468] DIPEA N,N-diisopropylethylamine, also called
Hunig's base [0469] DMA dimethylacetamide [0470] DMAP
4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine
[0471] DME dimethoxyethane [0472] DMF N,N-dimethylformamide [0473]
DMSO dimethyl sulfoxide [0474] eq or equiv equivalent [0475] (ES+)
electrospray ionization, positive mode [0476] Et ethyl [0477] EtOAc
ethyl acetate [0478] EtOH ethanol [0479] h hour(s) [0480] HATU
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium
3-oxid hexafluorophosphate [0481] HPLC high performance liquid
chromatography [0482] LC liquid chromatography [0483] m multiplet
[0484] m-CPBA 3-chloroperoxybenzoic acid [0485] Me methyl [0486]
MeCN acetonitrile [0487] MeOH methanol [0488] (M+H)+ protonated
molecular ion [0489] MHz megahertz [0490] min minute(s) [0491] MS
mass spectrometry [0492] Ms mesyl, also called methanesulfonyl
[0493] MsCl mesyl chloride, also called methanesulfonyl chloride
[0494] MTBE methyl tert-butyl ether, also called tert-butyl methyl
ether [0495] m/z mass-to-charge ratio [0496] NaO.sup.tBu sodium
tert-butoxide [0497] NBS 1-bromopyrrolidine-2,5-dione, also called
N-bromosuccinimide [0498] NCS 1-chloropyrrolidine-2,5-dione, also
called N-chlorosuccinimide [0499] NMP N-methylpyrrolidine [0500]
NMR nuclear magnetic resonance (spectroscopy) [0501] Pd(dba).sub.3
tris(dibenzylideneacetone) dipalladium(o) [0502] Pd(dppf)Cl.sub.2
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) [0503]
PE petroleum ether [0504] Ph phenyl [0505] PMB p-methoxybenzyl,
also called 4-methoxybenzyl [0506] prep-HPLC preparative high
performance liquid chromatography [0507] prep-TLC preparative thin
layer chromatography [0508] PTSA p-toluenesulfonic acid [0509] q
quartet [0510] RP reversed phase [0511] RT room temperature [0512]
s singlet [0513] Sept septuplet [0514] sat saturated [0515] SCX
solid supported cation exchange (resin) [0516] t triplet [0517] T3P
propylphosphonic anhydride [0518] TBME tert-butyl methyl ether,
also called methyl tert-butyl ether [0519] TEA triethylamine [0520]
TFA 2,2,2-trifluoroacetic acid [0521] THF tetrahydrofuran [0522]
TLC thin layer chromatography [0523] wt % weight percent or percent
by weight
[0524] Experimental Methods
[0525] Analytical Methods
[0526] NMR spectra were recorded at 300, 400 or 500 MHz (unless
stated otherwise) with chemical shifts reported in parts per
million. Spectra were measured at 298 K, unless indicated
otherwise, and were referenced relative to the solvent resonance.
Spectra were recorded using one of the following machines: [0527]
An Agilent VNMRS 300 instrument fitted with a 7.05 Tesla magnet
from Oxford instruments, indirect detection probe and direct drive
console including PFG module. [0528] An Agilent MercuryPlus 300
instrument fitted with a 7.05 Tesla magnet from Oxford instruments,
4 nuclei auto-switchable probe and Mercury plus console. [0529] A
Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program
control. [0530] A Bruker Avance III spectrometer at 400 MHz fitted
with a BBO 5 mm liquid probe. [0531] A Bruker Avance III HD
spectrometer at 500 MHz, equipped with a Bruker 5 mm
SmartProbe.TM..
[0532] LC-MS Methods: Using SHIMADZU LCMS-2020, Agilent 1200
LC/G1956A MSD and Agilent 1200G6110A, Agilent 1200 LC & Agilent
6110 MSD. Mobile Phase: A: 0.025% NH.sub.3.H.sub.2O in water (v/v);
B: acetonitrile. Column: Kinetex EVO C18 2.1.times.30 mm, 5
.mu.m.
[0533] Reversed Phase HPLC Conditions for the LCMS Analytical
Methods:
[0534] Methods 1a and 1b: Waters Xselect CSH C18 XP column, 2.5
.mu.m (4.6.times.30 mm) at 40.degree. C.; flow rate 2.5-4.5 mL
min.sup.-1 eluted with a water-acetonitrile gradient containing
either 0.1% v/v formic acid (Method 1a) or 10 mM ammonium
bicarbonate in water (Method 1b) over 4 minutes employing UV
detection at 254 nm. Gradient information: 0-3.00 min, ramped from
95% water-5% acetonitrile to 5% water-95% acetonitrile; 3.00-3.01
min, held at 5% water-95% acetonitrile, flow rate increased to 4.5
mL min.sup.-1; 3.01-3.50 min, held at 5% water-95% acetonitrile;
3.50-3.60 min, returned to 95% water-5% acetonitrile, flow rate
reduced to 3.50 mL min.sup.-1; 3.60-3.90 min, held at 95% water-5%
acetonitrile; 3.90-4.00 min, held at 95% water-5% acetonitrile,
flow rate reduced to 2.5 mL min.sup.-1.
[0535] HPLC and LC-MS were recorded on an Agilent 1290 series with
UV detector and HP 6130 MSD mass detector. Mobile phase A: ammonium
acetate (10 mM); water/MeOH/acetonitrile (900:60:40); mobile phase
B: ammonium acetate (10 mM); water/MeOH/acetonitrile (100:540:360);
column, Waters XBridge BEH C18 XP (2.1 .times.50 mm, 2.5
.mu.m).
TABLE-US-00001 Pump flow: 0.6 mL/min UV detection: 215, 238 nm
Injection volume: 0.2 .mu.L Run time: 4.0 min Column temperature:
35.degree. C. Mass detection: API-ES +ve and -ve
[0536] Pump Program:
TABLE-US-00002 Gradient Time (min) % A % B 0.0 80 20 0.5 80 20 2.0
0 100
[0537] Reversed Phase HPLC Conditions for the UPLC Analytical
Methods:
[0538] Methods 2a and 2b: Waters BEH C18 (2.1.times.30 mm, 1.7
.mu.m) at 40.degree. C.; flow rate 0.77 mL min.sup.-1 eluted with a
H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid
(Method 2a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 2b) over 3
min employing UV detection at 254 nm. Gradient information: 0-0.11
min, held at 95% water-5% acetonitrile, flow rate 0.77 mL
min.sup.-1; 0.11-2.15 min, ramped from 95% water-5% acetonitrile to
5% water-95% acetonitrile; 2.15-2.49 min, held at 5% water-95%
acetonitrile, flow rate 0.77 mL min.sup.-1; 2.49-2.56 min, returned
to 95% water-5% acetonitrile; 2.56-3.00 min, held at 95% water-5%
acetonitrile, flow rate reduced to 0.77 mL min.sup.-1.
[0539] Purification Methods
[0540] Method 1 (acidic preparation): Waters X-Select CSH column
C18, 5 m (19.times.50 mm), flow rate 28 mL/min eluting with a
water-acetonitrile gradient containing 0.1% v/v formic acid over
6.5 minutes using UV detection at 254 nm. Gradient information:
0.0-0.2 minutes, 20% acetonitrile; 0.2-5.5 minutes, ramped from 20%
acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, ramped from 40%
acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, held at 95%
acetonitrile.
[0541] Method 2 (basic preparation): Waters X-Bridge Prep column
C18, 5 .mu.m (19.times.50 mm), flow rate 28 mL/min eluting with a
10 mM ammonium bicarbonate-acetonitrile gradient over 6.5 minutes
using UV detection at 254 nm. Gradient information: 0.0-0.2
minutes, 10% acetonitrile; 0.2-5.5 minutes, ramped from 10%
acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, ramped from 40%
acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, held at 95%
acetonitrile.
[0542] Method 3: Phenomenex Gemini column, 10 .mu.m (150.times.25
mm), flow rate=25 mL/min eluting with a water-acetonitrile gradient
containing 0.04% NH.sub.3 at pH 10 over 9 minutes using UV
detection at 220 and 254 nm. Gradient information: 0-9 minutes,
ramped from 8% to 35% acetonitrile; 9-9.2 minutes, ramped from 35%
to 100% acetonitrile; 9.2-15.2 minutes, held at 100%
acetonitrile.
[0543] Method 4: Buchi Sepracore.RTM. X50 system driven by a C-605
pump module, C-620 Sepracore control package, C-640 UV photometer
detection unit and C-660 fraction collector.
[0544] Revelis C18 reversed-phase 12 g cartridge
TABLE-US-00003 Carbon loading 18% Surface area 568 m.sup.2/g Pore
diameter 65 Angstrom pH (5% slurry) 5.1 Average particle size 40
.mu.m
[0545] The column was conditioned before use with MeOH (5 min) then
brought to H.sub.2O (in 5 min) and kept 5 min at H.sub.2O. Flow
rate=30 mL/min.
[0546] Separation Runs:
TABLE-US-00004 Time (min) A: water (%) B: MeOH (%) 0 100 0 5 100 0
30 30 70 30.1 0 100 35 0 100
[0547] Detection wavelength: 215, 235, 254 and 280 nm. Before each
new run, the cartridge was cleaned using the conditioning
method.
Synthesis of Intermediates
Intermediate A1: 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene
##STR00032##
[0549] To a solution of phosgene (4.45 mL, 20% weight in toluene,
8.4 mmol) in ethyl acetate (90 mL) was added dropwise a solution of
1,2,3,5,6,7-hexahydro-s-indacen-4-amine (589 mg, 3.4 mmol) in ethyl
acetate (45 mL) at ambient temperature. The resulting reaction
mixture was then heated to reflux for 3 hours and upon cooling was
filtered and concentrated in vacuo to afford the title compound as
a brown oil (756 mg, 100%). The crude product was used directly in
the next step without further purification. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 6.8 (s, 1H), 2.89 (m, 8H) and 2.09 (m,
4H).
Intermediate A2:
4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile
Step A: 4-Fluoro-2-(prop-1-en-2-yl)aniline
##STR00033##
[0551] To a mixture of 2-bromo-4-fluoroaniline (39 g, 205.25 mmol,
1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane
(36.21 g, 215.51 mmol, 1.05 eq) and K.sub.2CO.sub.3 (70.92 g,
513.12 mmol, 2.5 eq) in dioxane (200 mL) and H.sub.2O (40 mL) was
added Pd(dppf)Cl.sub.2 (7.51 g, 10.26 mmol, 0.05 eq) under a
nitrogen atmosphere. Then the reaction mixture was stirred at
80.degree. C. for 5 hours. The reaction mixture was quenched by
addition of H.sub.2O (600 mL) and extracted with EtOAc (2.times.500
mL). The combined organic layers were washed with brine
(2.times.600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (SiO.sub.2, petroleum ether:
ethyl acetate 1:o to 100:1) to give the title compound (27 g, 77%
yield, 89% purity on LCMS) as a yellow oil.
[0552] .sup.1H NMR (CDCl.sub.3) .delta. 6.81-6.76 (m, 2H),
6.66-6.62 (m, 1H), 5.38 (s, 1H), 5.08 (s, 1H), 3.69 (br s, 2H) and
1.25 (s, 3H).
[0553] LCMS: m/z 152.2 (M+H)+(ES+).
Step B: 4-Fluoro-2-isopropylaniline
##STR00034##
[0555] To a solution of 4-fluoro-2-(prop-1-en-2-yl)aniline (21 g,
138.91 mmol, 1 eq) in MeOH (300 mL) was added Pd/C (2.1 g, 178.59
mmol, 10 wt % loading on activated carbon) under a nitrogen
atmosphere. The reaction mixture was degassed in vacuo and purged
with hydrogen several times. The reaction mixture was stirred at
25.degree. C. for 12 hours under hydrogen (50 psi). The reaction
mixture was filtered and the filtrate was concentrated in vacuo to
give the title compound (20 g, crude) as a yellow oil.
[0556] .sup.1H NMR (CDCl.sub.3) .delta. 6.86 (dd, 1H), 6.75-6.72
(m, 1H), 6.63-6.61 (m, 1H), 3.50 (br s, 2H), 2.95-2.84 (m, 1H) and
1.25 (d, 6H).
[0557] LCMS: m/z 154.2 (M+H).sup.+ (ES.sup.+).
Step C: 2-Bromo-4-fluoro-6-isopropylaniline
##STR00035##
[0559] To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55
mmol, 1 eq) in toluene (250 mL) was added NBS (23.24 g, 130.55
mmol, 1 eq) at 25.degree. C. The reaction mixture was stirred at
25.degree. C. for 10 minutes. The reaction mixture was poured into
H.sub.2O (300 mL) and extracted with EtOAc (2.times.250 mL). The
combined organic phases were washed with brine (2.times.400 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified by silica gel column chromatography
(SiO.sub.2, eluting only by using petroleum ether) to give the
title compound (30 g, 99%) as a black brown oil.
[0560] .sup.1H NMR (CDCl.sub.3) .delta. 6.99 (dd, 1H), 6.78 (dd,
1H), 3.91 (br s, 2H), 2.88-2.71 (m, 1H) and 1.17 (d, 6H).
[0561] LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).
Step D: 4-(2-Amino-5-fluoro-3-isopropylphenyl)picolinonitrile
##STR00036##
[0563] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (3.6 g,
15.51 mmol, 1 eq) and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile
(3.60 g, 15.67 mmol, 1.01 eq) in dioxane (90 mL) and H.sub.2O (9
mL) was added Na.sub.2CO.sub.3 (4.11 g, 38.78 mmol, 2.5 eq). Then
Pd(dppf)Cl.sub.2 (1.13 g, 1.55 mmol, 0.1 eq) was added to the
mixture under a nitrogen atmosphere. The resulting mixture was
stirred at 80.degree. C. for 2 hours under nitrogen. Then the
mixture was concentrated in vacuo. The residue was purified by
silica gel column chromatography (SiO.sub.2, petroleum ether: ethyl
acetate, 20:1 to 5:1) and then triturated with petroleum ether (10
mL) to give the title compound (2.65 g, 65% yield, 97% purity on
LCMS) as a yellow solid.
[0564] .sup.1HNMR (CDCl.sub.3) .delta. 8.79 (d, 1H), 7.86 (d, 1H),
7.65 (dd, 1H), 6.99 (dd, 1H), 6.70 (dd, 1H), 3.63 (br s, 2H),
2.98-2.87 (m, 1H) and 1.30 (d, 6H).
[0565] LCMS: m/z 256.2 (M+H).sup.+ (ES.sup.+).
Step E:
4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile
##STR00037##
[0567] To a solution of
4-(2-amino-5-fluoro-3-isopropylphenyl)picolinonitrile (1 g, 3.92
mmol, 1 eq) in THF (40 mL) was added TEA (793 mg, 7.83 mmol, 2 eq).
To the above mixture was added triphosgene (465 mg, 1.57 mmol, 0.4
eq) in portions at 5.degree. C. Then the mixture was stirred at
70.degree. C. for 1 hour. The mixture was diluted with EtOAc (200
mL) and then filtered through silica gel. The filtrate was
concentrated in vacuo to give the title compound (1.2 g, crude) as
a yellow solid, which was used directly in the next step.
Intermediate Ag:
4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine
Step A: 4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline
##STR00038##
[0569] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (12 g,
51.70 mmol, 1 eq) in dioxane (240 mL) and H.sub.2O (48 mL) was
added (2-methoxypyridin-4-yl)boronic acid (9.49 g, 62.04 mmol, 1.2
eq) and Na.sub.2CO.sub.3 (13.70 g, 129.26 mmol, 2.5 eq). The
reaction mixture was purged with nitrogen three times. Then
Pd(dppf)Cl.sub.2 (3.78 g, 5.17 mmol, 0.1 eq) was added to the
mixture under a nitrogen atmosphere. The resulting mixture was
heated at 80.degree. C. for 2 hours. The reaction mixture was
quenched with H.sub.2O (800 mL) and extracted with EtOAc
(2.times.600 mL). The combined organic layers were washed with
brine (2.times.800 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (SiO.sub.2, petroleum
ether: ethyl acetate, 70:1 to 10:1) and then triturated with hexane
(100 mL) to give the title compound (10.05 g, 72% yield, 96% purity
on LCMS).
[0570] .sup.1H NMR (CDCl.sub.3) .delta. 8.24 (d, 1H), 6.97 (d, 1H),
6.93 (d, 1H), 6.83 (s, 1H), 6.73-6.70 (m, 1H), 3.99 (s, 3H), 3.66
(br s, 2H), 2.97-2.89 (m, 1H) and 1.29 (dd, 6H).
[0571] LCMS: m/z 261.1 (M+H).sup.+ (ES.sup.+).
Step B:
4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine
##STR00039##
[0573] To a solution of
4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) aniline (1 g, 3.84
mmol, 1 eq) in THF (40 mL) was added TEA (777 mg, 7.68 mmol, 2 eq).
Then triphosgene (456 mg, 1.54 mmol, 0.4 eq) was added in portions
at 5.degree. C. The mixture was stirred at 70.degree. C. for 1
hour. The mixture was diluted with EtOAc (200 mL) and filtered
through silica gel. The filtrate was concentrated in vacuo to give
the title compound (1.1 g, crude) as a yellow oil, which was used
directly in the next step.
Intermediate A4:
4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine
Step A: 4-Nitro-2,3-dihydro-1H-indene
##STR00040##
[0575] To a mixture of 2,3-dihydro-1H-indene (60 g, 507.72 mmol,
62.50 mL, 1 eq) in concentrated H.sub.2SO.sub.4 (30 mL) was added a
mixture of HNO.sub.3 (50 mL, 69 wt % in water) and concentrated
H.sub.2SO.sub.4 (50 mL) dropwise at 0.degree. C. over a period of
3.5 hours. The reaction mixture was stirred at 0.degree. C. for 0.5
hour. Then the reaction mixture was poured into ice water (600 mL)
and extracted with ethyl acetate (2.times.400 mL). The combined
organic layers were washed with water (500 mL), saturated aqueous
NaHCO.sub.3 solution (500 mL) and brine (2.times.500 mL). The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (SiO.sub.2, petroleum ether: ethyl acetate,
1:0 to 100:1) to give the title compound (55 g, 66%) as a
colourless oil.
[0576] .sup.1H NMR (CDCl.sub.3): .delta. 7.98 (d, 1H), 7.51 (d,
1H), 7.30 (t, 1H), 3.41 (t, 2H), 302 (t, 2H) and 2.22-2.20 (m,
2H).
Step B: 2,3-Dihydro-1H-inden-4-amine
##STR00041##
[0578] To a solution of 4-nitro-2,3-dihydro-1H-indene (55 g,
contained another regio-isomer) in MeOH (500 mL) was added Pd/C (5
g, 10 wt % loading on activated carbon) under N.sub.2 atmosphere.
The suspension was degassed under vacuum and purged with H.sub.2
several times. The reaction mixture was stirred under H.sub.2 (50
psi) at 20.degree. C. for 12 hours. The reaction mixture was
filtered and the filtrate was concentrated in vacuo. The residue
was purified by silica gel column chromatography (SiO.sub.2,
petroleum ether: ethyl acetate, 1:o to 100:4) to give the title
compound (19.82 g, 43% yield, 96.39% purity on LCMS) as a brown
oil.
[0579] .sup.1H NMR (CDCl.sub.3): .delta. 7.01 (t, 1H), 6.71 (d,
1H), 6.51 (d, 1H), 3.57 (br s, 2H), 2.93 (t, 2H), 2.75 (t, 2H) and
2.16-2.08 (m, 2H).
[0580] LCMS: m/z 134.2 (M+H).sup.+ (ES.sup.+).
Step C: N-(2,3-Dihydro-1H-inden-4-yl)acetamide
##STR00042##
[0582] To a solution of 2,3-dihydro-1H-inden-4-amine (19.8 g,
148.66 mmol, 1 eq) and TEA (19.56 g, 193.26 mmol, 1.3 eq) in DCM
(300 mL) was added dropwise Ac.sub.2O (17.45 g, 170.96 mmol, 1.15
eq) over 6 minutes at 0.degree. C. Then the reaction mixture was
warmed to 16.degree. C. and stirred for 1.4 hours. The mixture was
poured into water (500 mL) and extracted with DCM (2.times.300 mL).
The combined organic phases were washed with brine (2.times.500
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give the title compound (25.74 g, 96%
yield, 96.69% purity on LCMS) as a white solid.
[0583] .sup.1H NMR (CDCl.sub.3): .delta. 7.70 (d, 1H), 7.15 (t,
1H), 7.02 (d, 1H), 2.95 (t, 2H), 2.81 (t, 2H), 2.18 (s, 3H) and
2.15-2.08 (m, 2H).
[0584] LCMS: m/z 176.2 (M+H).sup.+ (ES.sup.+)
Step D: N-(5-Bromo-2,3-dihydro-1H-inden-4-yl)acetamide
##STR00043##
[0586] N-(2,3-dihydro-1H-inden-4-yl)acetamide (34.6 g, 197.46 mmol,
1 eq), p-toluenesulfonic acid (18.70 g, 108.60 mmol, 0.55 eq) and
Pd(OAc).sub.2 (2.22 g, 9.87 mmol, 0.05 eq) were suspended in
toluene (400 mL) and stirred at 20.degree. C. for 0.5 hour under
air atmosphere. NBS (38.66 g, 217.20 mmol, 1.1 eq) was added. Then
the reaction mixture was stirred at 20.degree. C. for 2 hours. The
reaction mixture was poured into water (500 mL) and extracted with
ethyl acetate (2.times.500 mL). The combined organic phases were
washed with brine (2.times.500 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by silica gel column chromatography (SiO.sub.2,
petroleum ether: ethyl acetate, 10: 1 to 2:1) to give the title
compound (13.9 g, 27% yield, 98.1% purity on LCMS) as a white
solid.
[0587] .sup.1H NMR (CDCl.sub.3): .delta. 7.33 (d, 1H), 7.16 (s,
1H), 6.98 (d, 1H), 2.92-2.83 (m, 4H), 2.21 (s, 3H) and 2.10-2.02
(m, 2H).
[0588] LCMS: m/z 254.1 (M+H).sup.+ (ES.sup.+).
Step E: 5-Bromo-2,3-dihydro-1H-inden-4-amine
##STR00044##
[0590] A mixture of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide
(45.68 g, 179.76 mmol, 1 eq) in EtOH (200 mL) and concentrated HCl
(300 mL, 36 wt % in water) was stirred at 80.degree. C. for 36
hours. The reaction mixture was cooled to 0.degree. C. in an ice
bath and some solid precipitated. The suspension was filtered. The
filter cake was washed with ice water (50 mL) and dried in vacuo to
give the title compound (34.1 g, 72% yield, 94.08% purity on LCMS,
HCl salt) as a grey solid.
[0591] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.67 (br s, 2H), 7.24
(d, 1H), 6.69 (d, 1H), 2.85 (t, 2H), 2.79 (t, 2H) and 2.04-1.96 (m,
2H).
[0592] LCMS: m/z 212.0 (M+H).sup.+ (ES.sup.+).
Step F: 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine
##STR00045##
[0594] A solution of (2-methoxypyridin-4-yl)boronic acid (25.11 g,
164.15 mmol, 1.2 eq), 5-bromo-2,3-dihydro-1H-inden-4-amine (34 g,
136.80 mmol, 1 eq, HCl salt) and K.sub.2CO.sub.3 (60.50 g, 437.74
mmol, 3.2 eq) in dioxane (500 mL) and H.sub.2O (100 mL) was
degassed with nitrogen for 15 minutes before
Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (6 g, 7.35 mmol, 0.053 eq) was
added. The reaction mixture was heated to 80.degree. C. for 12
hours. The mixture was poured into water (500 mL) and extracted
with ethyl acetate (2.times.500 mL). The combined organic phases
were washed with brine (2.times.700 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by silica gel column chromatography (SiO.sub.2,
petroleum ether: ethyl acetate, 1:0 to 10:1) to give the title
compound (27.4 g, 79% yield, 95% purity on LCMS) as a white
solid.
[0595] .sup.1H NMR (CDCl.sub.3): .delta. 8.22 (d, 1H), 7.03-7.00
(m, 1H), 6.99 (d, 1H), 6.87 (s, 1H), 6.77 (d, 1H), 3.99 (s, 3H),
3.77 (br s, 2H), 2.97 (t, 2H), 2.77 (t, 2H) and 2.21-2.13 (m,
2H).
[0596] LCMS: m/z 241.2 (M+H).sup.+ (ES.sup.+).
Step G:
4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine
##STR00046##
[0598] To a solution of
5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (11 g, 45.78
mmol, 1 eq) and TEA (5.10 g, 50.35 mmol, 1.1 eq) in THF (275 mL)
was added bis(trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36
eq) in portions at o oC. Then the reaction mixture was stirred at
16.degree. C. for 0.5 hour. The reaction mixture was filtered and
the filter cake was washed with THF (2 L). The filtrate was
concentrated in vacuo to give the title compound (9.04 g, 74%) as a
light yellow solid.
[0599] .sup.1H NMR (CDCl.sub.3): .delta. 8.28 (d, 1H), 7.20-7.16
(m, 3H), 7.02 (s, 1H), 4.16 (s, 3H), 3.04-2.99 (m, 4H) and
2.23-2.15 (m, 2H).
Intermediate A.:
4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine
Step A: 7-Fluoro-4-nitro-2,3-dihydro-1H-inden-1-one
##STR00047##
[0601] To a mixture of 7-fluoro-2,3-dihydro-1H-inden-1-one (9.5 g,
63.27 mmol, 1 eq) in concentrated H.sub.2SO.sub.4 (100 mL) was
added dropwise a solution of HNO.sub.3 (5.37 mL, 82.25 mmol, 69 wt
% in water, 1.3 eq) in concentrated H.sub.2SO.sub.4 (20 mL) at
-15.degree. C. Then the reaction mixture was stirred at 0.degree.
C. for 0.5 hour. The mixture was quenched with water (500 mL) at
0.degree. C., and then extracted with EtOAc (3.times.300 mL). The
combined organic phases were dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was purified by
silica gel column chromatography (SiO.sub.2, petroleum ether: ethyl
acetate, 10:1 to 3:1) to give the title compound (11.4 g, 92%) as a
yellow solid.
[0602] .sup.1H NMR (CDCl.sub.3) .delta. 8.51 (dd, 1H), 7.22 (t,
1H), 3.69-3.65 (m, 2H) and 2.88-2.82 (m, 2H).
Step B: 7-Fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol
##STR00048##
[0604] To a mixture of 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-one
(30 g, 153.73 mmol, 1 eq) in EtOH (450 mL) was added NaBH.sub.4
(11.63 g, 307.46 mmol, 2 eq) in portions. The reaction mixture was
stirred at 15.degree. C. for 1 hour. Then the mixture was poured
into water (500 mL) and extracted with DCM (2.times.200 mL). The
combined organic phases were washed with brine (200 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give the title compound (30 g, crude) as brown oil.
[0605] .sup.1H NMR (CDCl.sub.3) .delta. 8.21 (dd, 1H), 7.08 (t,
1H), 5.59-5.56 (m, 1H), 3.66-3.59 (m, 1H), 3.44-3.39 (m, 1H),
2.56-2.51 (m, 1H) and 2.22-2.17 (m, 2H).
Step C: 4-Fluoro-7-nitro-2,3-dihydro-1H-indene
##STR00049##
[0607] To a mixture of 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol
(4.5 g, 22.82 mmol, 1 eq) in TFA (20 mL) was added Et.sub.3SiH
(7.96 g, 68.47 mmol, 3 eq) in one portion. The reaction mixture was
stirred at 25.degree. C. for 12 hours. Then the mixture was
quenched with water (100 mL) and extracted with EtOAc (3.times.100
mL). The combined organic layers were washed with saturated aqueous
NaHCO.sub.3 solution (2.times.100 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the
title compound (5 g, crude) as brown oil.
[0608] .sup.1H NMR (CDCl.sub.3) .delta. 8.06 (dd, 1H), 7.01 (t,
1H), 3.46 (t, 2H), 3.04 (t, 2H) and 2.25-2.20 (m, 2H).
Step D: 7-Fluoro-2,3-dihydro-1H-inden-4-amine
##STR00050##
[0610] To a mixture of 4-fluoro-7-nitro-2,3-dihydro-1H-indene (5 g,
27.60 mmol, 1 eq) in MeOH (50 mL) was added Pd/C (0.5 g, 10 wt %
loading on activated carbon) at 25.degree. C. under a nitrogen
atmosphere. Then the reaction mixture was stirred at 25.degree. C.
for 12 hours under hydrogen (15 psi). The mixture was filtered and
the filtrate was concentrated in vacuo. The residue was purified by
silica gel column chromatography (SiO.sub.2, petroleum ether: ethyl
acetate, 50:1 to 10:1) to give the title compound (1.8 g, 43%) as a
brown solid.
[0611] .sup.1H NMR (CDCl.sub.3) .delta. 6.69 (t, 1H), 6.44 (dd,
1H), 3.47 (br s, 2H), 2.95 (t, 2H), 2.75 (t, 2H) and 2.19-2.11 (m,
2H).
Step E: 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine
##STR00051##
[0613] To a solution of 7-fluoro-2,3-dihydro-1H-inden-4-amine (8.3
g, 54.90 mmol, 1 eq) in toluene (100 mL) was added NBS (10.26 g,
57.65 mmol, 1.05 eq) in one portion at 25.degree. C. The reaction
mixture turned dark brown immediately and then the mixture was
stirred at 25.degree. C. for 30 minutes. The reaction mixture was
quenched with saturated aqueous Na.sub.2SO.sub.3 solution (200 mL)
and extracted with EtOAc (2.times.100 mL). The combined organic
phases were washed with brine (100 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by silica gel column chromatography (SiO.sub.2,
petroleum ether: ethyl acetate, 1:o to 20:1) to give the title
compound (8.51 g, 67%) as a brown solid.
[0614] .sup.1H NMR (CDCl.sub.3) .delta. 6.99 (d, 1H), 3.81 (br s,
2H), 2.92 (t, 2H), 2.78 (t, 2H) and 2.21-2.13 (m, 2H).
Step F: 7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine
##STR00052##
[0616] To a mixture of
5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (3.5 g, 15.21 mmol, 1
eq) and pyridin-4-ylboronic acid (1.96 g, 15.97 mmol, 1.05 eq) in
dioxane (500 mL) and H.sub.2O (5 mL) was added K.sub.2CO.sub.3
(6.31 g, 45.64 mmol, 3 eq) and Pd(dppf)Cl.sub.2 (1.11 g, 1.52 mmol,
0.1 eq) in one portion under a nitrogen atmosphere. Then the
reaction mixture was heated to 80.degree. C. for 12 hours. The
reaction mixture was filtered. The filtrate was diluted with water
(50 mL) and extracted with EtOAc (3.times.100 mL). The combined
organic phases were washed with brine (100 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(SiO.sub.2, petroleum ether: ethyl acetate, 10:1 to 2:1) to give
the title compound (1.7 g, 45% yield, 90.98% purity on HPLC) as a
brown solid.
[0617] .sup.1H NMR (CDCl.sub.3) .delta. 8.68 (dd, 2H), 7.40 (dd,
2H), 6.72 (d, 1H), 3.76 (br s, 2H), 3.01 (t, 2H), 2.80 (t, 2H) and
2.26-2.18 (m, 2H).
Step G:
4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine
##STR00053##
[0619] To a solution of
7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (400 mg,
1.75 mmol, 1 eq) and TEA (355 mg, 3.50 mmol, 2 eq) in THF (30 mL)
was added bis(trichloromethyl) carbonate (208 mg, 700.94 .mu.mol,
0.4 eq) at 0.degree. C. The reaction mixture was stirred at
70.degree. C. for 30 minutes. Then the reaction mixture was
filtered through a pad of silica gel and the filter cake was washed
with THF (20 mL). The filtrate was concentrated in vacuo to reduce
to 10 mL, which was used directly in the next step.
Intermediate P1: (3,5-Dichlorophenyl)methanesulfonamide
##STR00054##
[0621] To a solution of saturated ammonia in THF (5 mL) was added
dropwise a solution of (3,5-dichlorophenyl)methanesulfonyl chloride
(200 mg, 770.60 .mu.mol, 1 eq) in THF (1 mL). The mixture was
stirred at 20.degree. C. for 1 hour and then concentrated under
reduced pressure. The residue was diluted with water (5 mL) and
then the mixture was extracted into ethyl acetate (2.times.5 mL).
The combined organic layers were washed with brine (5 mL), dried
(anhydrous Na.sub.2SO.sub.4), filtered and concentrated in vacuo to
give the title compound (180 mg, 97%) as a white solid.
[0622] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.42 (d, 1H), 7.35
(d, 2H), 4.58 (br s, 2H) and 4.28 (s, 2H).
Intermediate P2: 2-Methylpropane-1-sulfonamide
##STR00055##
[0624] A solution of 2-methylpropane-1-sulfonyl chloride (1.5 g,
9.58 mmol, 1 eq) in THF (20 mL) was cooled to 0.degree. C. Then
NH.sub.3 (15 psi) was bubbled into the mixture at 0.degree. C. for
10 minutes. The mixture was stirred at 0.degree. C. for another 10
minutes. The reaction mixture was filtered and the filtrate was
concentrated in vacuo to give the title compound (1 g, 76%) as a
colourless oil.
[0625] .sup.1H NMR (DMSO-d.sub.6): .delta. 6.72 (s, 2H), 2.86 (d,
2H), 2.19-2.07 (m, 1H) and 1.01 (d, 6H).
Intermediate P3: 2-Phenylethanesulfonamide
##STR00056##
[0627] NH.sub.3 was bubbled into THF (10 mL) at -78.degree. C. for
5 minutes. Then a solution of 2-phenylethanesulfonyl chloride (0.5
g, 2.44 mmol, 1 eq) in THF (10 mL) was added to the NH.sub.3/THF
solution at 25.degree. C. The resulting mixture was stirred for 12
minutes. The mixture was filtered and the filtrate was concentrated
in vacuo to give the title compound (0.38 g, 84%) as a white
solid.
[0628] .sup.1H NMR (CDCl.sub.3): .delta. 7.38-7.33 (m, 2H),
7.29-7.24 (m, 3H), 4.42 (br s, 2H), 3.45-3.40 (m, 2H) and 3.22-3.17
(m, 2H).
[0629] LCMS: m/z 208.1 (M+Na).sup.+ (ES.sup.+).
Intermediate P4: 1-Phenylethanesulfonamide
Step A: N,N-Bis(4-methoxybenzyl)-1-phenylmethanesulfonamide
##STR00057##
[0631] To a solution of bis(4-methoxybenzyl)amine (4.05 g, 15.74
mmol, 1 eq) in DCM (40 mL) was added TEA (3.18 g, 31.47 mmol, 2 eq)
and phenylmethanesulfonyl chloride (3 g, 15.74 mmol, 1 eq). The
mixture was stirred at 20.degree. C. for 12 hours. The reaction
mixture was concentrated in vacuo. The residue was treated with
water (50 mL) and extracted with EtOAc (2.times.50 mL). The organic
layers were dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The residue was purified by silica gel column
chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 5:1 to
3:1) to give the title compound (4 g, 62%) as a yellow solid.
[0632] .sup.1H NMR (CDCl.sub.3): .delta. 7.24-7.20 (m, 3H), 7.11
(dd, 4H), 7.00-6.95 (m, 2H), 6.80 (dd, 4H), 4.03 (s, 2H), 3.96 (s,
4H) and 3.74 (s, 6H).
Step B: N,N-Bis(4-methoxybenzyl)-1-phenylethanesulfonamide
##STR00058##
[0634] To a solution of
N,N-bis(4-methoxybenzyl)-1-phenylmethanesulfonamide (1 g, 2.43
mmol, 1 eq) in THF (10 mL) was added LDA (2 M, 1.34 mL, 1.1 eq) at
-78.degree. C. under N.sub.2 atmosphere. The mixture was stirred at
-78.degree. C. for 1 hour. Iodomethane (379 mg, 2.67 mmol, 1.1 eq)
was added and the resulting mixture was stirred at 20.degree. C.
for 2 hours. The reaction mixture was quenched with saturated
aqueous NH.sub.4Cl solution (20 mL) and then concentrated in vacuo
to remove THF. The mixture was treated with water (10 mL) and
extracted with EtOAc (3.times.15 mL). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified by silica gel column chromatography
(SiO.sub.2, petroleum ether: ethyl acetate, 1:o to 5:1) to give the
title compound (0.9 g, 87%) as a white solid.
[0635] .sup.1H NMR (CDCl.sub.3): .delta. 7.33-7.28 (m, 3H), 7.14
(d, 4H), 7.10-7.08 (m, 2H), 6.86 (dd, 4H), 4.09 (d, 2H), 4.03-4.01
(m, 1H), 3.83 (s, 6H), 3.76 (d, 2H) and 1.79 (d, 3H).
Step C: 1-Phenylethanesulfonamide
##STR00059##
[0637] To a solution of
N,N-bis(4-methoxybenzyl)-1-phenylethanesulfonamide (900 mg, 2.11
mmol, 1 eq) in DCM (30 mL) was added TFA (46.20 g, 405.19 mmol,
191.58 eq). The mixture was stirred at 20.degree. C. for 12 hours.
The reaction mixture was concentrated in vacuo. The residue was
treated with MeOH (15 mL). The suspension was filtered and the
filtrate was concentrated in vacuo. The residue was triturated with
a mixture of petroleum ether and ethyl acetate (v:v=20:1, 10 mL) to
give the title compound (300 mg, 77%) as a white solid.
[0638] .sup.1H NMR (CDCl.sub.3): .delta. 7.47-7.39 (m, 5H), 4.46
(br s, 2H), 4.29 (q, 1H) and 1.82 (d, 3H).
[0639] LCMS: m/z 208.1 (M+Na).sup.+ (ES.sup.+).
Intermediate P5: 3-Azidopropane-1-sulfonamide
##STR00060##
[0641] To a solution of 3-chloropropane-1-sulfonamide (200 mg, 1.3
mmol) in acetone (10 mL) was added sodium azide (200 mg, 3 mmol) in
water (1 mL). The mixture was refluxed for 36 hours. The solvents
were evaporated. The residue was triturated with THF. The THF layer
was filtered and evaporated to afford the title compound as a
yellow oil (200 mg, 96%).
[0642] .sup.1H NMR (CD.sub.3OD) .delta. 3.51 (t, 2H), 3.17 (t, 2H),
2.07 (m, 2H).
PREPARATION OF EXAMPLES
Example 1:
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-phenyl
Methanesulfonamide, Potassium Salt
##STR00061##
[0644] To a cooled (o .degree. C.) solution of
phenylmethanesulfonamide (40 mg, 0.23 mmol) in THF (2.5 mL) was
added potassium tert-butoxide (26 mg, 0.23 mmol). The ice bath was
removed and the reaction mixture was stirred whilst being allowed
to warm to room temperature over 40 minutes. A solution of
4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1; 46
mg, 0.23 mmol) in THF (1 mL) was added and the mixture was stirred
overnight at room temperature. The reaction mixture was
concentrated in vacuo and DMSO (1 mL) was added. The suspension was
filtered over cotton wool and subsequently submitted for
purification by reversed phase column chromatography (see
"Experimental Methods") to afford the title compound (34 mg; 40%)
as a white solid.
[0645] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.43 (m, 2H), 7.28
(m, 3H), 6.86 (s, 1H), 4.45 (s, 2H), 2.82 (m, 8H) and 2.02 (m,
4H).
[0646] LCMS: m/z 371 (M+H).sup.+ (ES.sup.+); 369 (M-H).sup.-
(ES.sup.-).
Example 2:
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-methylpro-
pane-1-sulfonamide, Potassium Salt
##STR00062##
[0648] Prepared as described for
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-phenyl
methanesulfonamide, potassium salt (Example 1) using
4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and
2-methylpropane-1-sulfonamide (Intermediate P2) to afford the title
compound (52%) as a white solid.
[0649] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 6.86 (s, 1H), 3.11
(d, 2H), 2.82 (m, 8H), 2.22 (m, 1H), 2.02 (m, 4H) and 1.08 (d,
6H).
[0650] LCMS: m/z 337 (M+H).sup.+ (ES.sup.+); 335 (M-H).sup.-
(ES.sup.-).
Example 3:
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfon-
amide
##STR00063##
[0652] Ethene sulfonamide (0.2 g, 1.3 mmol) was dissolved in THF
(2.5 mL), the mixture cooled to 0.degree. C. and potassium
t-butoxide (0.21 g, 1.9 mmol) added. After stirring at 0.degree. C.
for 45 minutes 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene
(Intermediate A1) (0.27 g, 1.4 mmol) in THF (2.5 mL) was added
dropwise and the mixture stirred for 20 hours at room temperature.
The resulting mixture was worked-up by evaporation in vacuo, taken
up in DMSO (2-3 mL) and purified by column chromatography (RP-ISCO:
40 g RP-Silica column, eluent 0-70% methanol-water). The first and
main fraction afforded the title compound (68 mg, 16%) after
freeze-drying in 97% purity.
[0653] HPLC-MS: 97% (ELSD), mass 306+1 (ACPI pos.).
[0654] .sup.1H NMR (300 MHz, DMSO-d6) .delta. 7.31 (s, 1H), 6.86
(dd, J=16.9, 10.0 Hz, 1H), 6.77 (s, 1H), 5.71 (d, J=17.2 Hz, 1H),
5.40 (d, J=9.9 Hz, 1H), 2.73 (dt, J=17.8, 7.4 Hz, 9H), 1.92 (q,
J=7.3 Hz, 4H).
Example 4:
1-(3,5-Dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl-
)carbamoyl)methanesulfonamide, Sodium Salt
##STR00064##
[0656] To a solution of (3,5-dichlorophenyl)methanesulfonamide
(Intermediate Pt) (180 mg, 749.7 .mu.mol) in THF (5 mL) was added
sodium methoxide (40.5 mg, 749.7 .mu.mol) at 20.degree. C. After
stirring for 15 minutes,
4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1)
(149.4 mg, 749.67 .mu.mol) was added to the mixture. The mixture
was stirred at 20.degree. C. for 15 hours and then filtered. The
collected solid was triturated with ethyl acetate (3.times.5 mL)
and the combined layers were concentrated in vacuo to give the
title compound (300 mg, 87%) as a white solid.
[0657] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.45-7.44 (m,
1H), 7.32-7.28 (m, 3H), 6.79 (s, 1H), 4.28 (s, 2H), 2.77-2.73 (m,
8H) and 1.95-1.91 (m, 4H).
[0658] LCMS: m/z 439 (M+H).sup.+ (ES.sup.+).
Example 5:
1-(4-Chlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)car-
bamoyl)methanesulfonamide, Sodium Salt
##STR00065##
[0660] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (53 mg, 40%) as a white solid.
[0661] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.30-7.29 (m,
4H), 7.21 (br s, 1H), 6.78 (s, 1H), 4.22 (s, 2H), 2.77-2.70 (m, 8H)
and 1.95-1.92 (m, 4H).
[0662] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+).
Example 6:
1-(3,4-Dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl-
)carbamoyl)methanesulfonamide, Sodium Salt
##STR00066##
[0664] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (24 mg, 11%) as a white solid.
[0665] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.52-7.50 (m,
2H), 7.28-7.23 (m, 2H), 6.78 (s, 1H), 4.26 (s, 2H), 2.77-2.72 (m,
8H) and 1.95-1.91 (m, 4H).
[0666] LCMS: m/z 439 (M+H).sup.+ (ES.sup.+).
Example 7:
1-(4-Fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)car-
bamoyl)methanesulfonamide, Sodium Salt
##STR00067##
[0668] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (125 mg, 61%) as a white solid.
[0669] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.34-7.30 (m,
3H), 7.07 (t, 2H), 6.79 (s, 1H), 4.20 (s, 2H), 2.79-2.70 (m, 8H)
and 1.95-1.91 (m, 4H).
[0670] LCMS: m/z 389 (M+H).sup.+ (ES.sup.+).
Example 8:
1-(4-Cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carb-
amoyl)methanesulfonamide, Sodium Salt
##STR00068##
[0672] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (99 mg, 40%) as a white solid.
[0673] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.72 (d, 2H),
7.47 (d, 2H), 7.24 (br s, 1H), 6.78 (s, 1H), 4.34 (s, 2H),
2.77-2.69 (m, 8H) and 1.95-1.91 (m, 4H).
[0674] LCMS: m/z 396 (M+H)+(ES.sup.+).
Example 9: Methyl
4-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)methyl)b-
enzoate, Sodium Salt
##STR00069##
[0676] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (125 mg, 72%) as a white solid.
[0677] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.84 (d, 2H),
7.44 (d, 2H), 7.26 (br s, 1H), 6.79 (s, 1H), 4.32 (s, 2H), 3.84 (s,
3H), 2.79-2.70 (m, 8H) and 1.95-1.91 (m, 4H).
[0678] LCMS: m/z 429 (M+H).sup.+ (ES.sup.+).
Example 10:
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(4-(trifluoromethyl-
)phenyl)methanesulfonamide, Sodium Salt
##STR00070##
[0680] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (102 mg, 29%) as a white solid.
[0681] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.60 (d, 2H),
7.51 (d, 2H), 7.24 (br s, 1H), 6.78 (s, 1H), 4.33 (s, 2H),
2.77-2.70 (m, 8H) and 1.95-1.91 (m, 4H).
[0682] LCMS: m/z 439 (M+H).sup.+ (ES.sup.+).
Example 11:
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(3-methoxyphenyl)me-
thanesulfonamide, Sodium Salt
##STR00071##
[0684] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (172 mg, 31%) as a white solid.
[0685] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.30-7.29 (m,
4H), 7.25 (br s, 1H), 6.78 (s, 1H), 4.21 (s, 2H), 3.33 (s, 3H),
2.77-2.72 (m, 8H) and 1.95-1.91 (m, 4H).
[0686] LCMS: m/z 401 (M+H).sup.+ (ES.sup.+).
Example 12:
1-(4-Chloro-2-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carb-
amoyl)methanesulfonamide, Sodium Salt
##STR00072##
[0688] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (198 mg, 67%) as a white solid.
[0689] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.43-7.33 (m,
1H), 7.32-7.30 (m, 2H), 7.21-7.18 (m, 1H), 6.79 (s, 1H), 4.27 (s,
2H), 2.77-2.72 (m, 8H) and 1.95-1.91 (m, 4H).
[0690] LCMS: m/z 423 (M+H).sup.+ (ES.sup.+).
Example 13:
1-(4-Chloro-3-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carb-
amoyl)methanesulfonamide, Sodium Salt
##STR00073##
[0692] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (200 mg, 53%) as a white solid.
[0693] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.48-7.44 (m,
1H), 7.31-7.27 (m, 2H), 7.16-7.14 (m, 1H), 6.79 (s, 1H), 4.25 (s,
2H), 2.78-2.69 (m, 8H) and 1.95-1.91 (m, 4H).
[0694] LCMS: m/z 423 (M+H).sup.+ (ES.sup.+).
Example 14:
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(p-tolyl)methanesul-
fonamide, Sodium Salt
##STR00074##
[0696] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (234 mg, 60%) as a white solid.
[0697] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.20-7.17 (m,
3H), 7.06-7.04 (m, 2H), 6.78 (s, 1H), 4.16 (s, 2H), 2.79-2.71 (m,
8H), 2.27 (S, 3H) and 1.95-1.92 (m, 4H).
[0698] LCMS: m/z 385 (M+H).sup.+ (ES.sup.+).
Example 15:
1-(2-Chlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)met-
hanesulfonamide, Sodium Salt
##STR00075##
[0700] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (36 mg, 34%) as a white solid.
[0701] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.50-7.39 (m,
1H), 7.38-7.36 (m, 1H), 7.29, (br s, 1H), 7.25-7.22 (m, 2H), 6.78
(s, 1H), 4.43 (s, 2H), 2.77-2.73 (m, 8H) and 1.95-1.92 (m, 4H).
[0702] LCMS: m/z 405 (M+H).sup.+ (ES.sup.+).
Example 16:
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-(trifluoromethyl-
)phenyl)methanesulfonamide, Sodium Salt
##STR00076##
[0704] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (21 mg, 15%) as a white solid.
[0705] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.77 (d, 1H),
7.65 (d, 1H), 7.57-7.55 (m, 1H), 7.45-7.43 (m, 1H), 7.36 (m, 1H),
6.79 (s, 1H), 4.47 (s, 2H), 2.80-2.75 (m, 8H) and 1.95-1.92 (m,
4H).
[0706] LCMS: m/z 439 (M+H).sup.+ (ES.sup.+).
Example 17:
1-(2-Bromophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)meth-
anesulfonamide, Sodium Salt
##STR00077##
[0708] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (85 mg, 87%) as a white solid.
[0709] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.57-7.53 (m,
2H), 7.37 (br s, 1H), 7.28-7.26 (m, 1H), 7.18-7.16 (m, 1H), 6.79
(s, 1H), 4.44 (s, 2H), 2.79-2.74 (m, 8H) and 1.98-1.90 (m, 4H).
[0710] LCMS: m/z 451 (M+H).sup.+ (ES.sup.+).
Example 18: Methyl 2-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)
carbamoyl)sulfamoyl)methyl)benzoate
##STR00078##
[0712] To a solution of methyl 2-(sulfamoylmethyl)benzoate (100 mg,
436.20 .mu.mol) in THF (4 mL) was added sodium methoxide (23.56 mg,
436.20 .mu.mol). The mixture was stirred at 20.degree. C. for 30
minutes before 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene
(Intermediate A1) (104.29 mg, 523.44 .mu.mol, 1.2 eq) was added.
The reaction mixture was stirred at 20.degree. C. for 16 hours and
then concentrated in vacuo. The crude product was purified by
prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 .mu.m; mobile
phase: [water (0.04% NH.sub.3H.sub.2O+10 mM
NH.sub.4HCO.sub.3)--acetonitrile]; B %: 20%-50%, 12 min) to give
the title compound (46 mg, 25%) as a white solid.
[0713] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.17 (br s,
1H), 7.88-7.86 (m, 2H), 7.63-7.61 (m, 1H), 7.57-7.55 (m, 1H),
7.42-7.40 (m, 1H), 6.98 (s, 1H), 5.19 (s, 2H), 3.79 (s, 3H),
2.85-2.81 (m, 4H), 2.74-2.72 (m, 4H) and 2.05-1.99 (m, 4H).
[0714] LCMS: m/z 451 (M+Na).sup.+ (ES.sup.+).
Example 19:
1-(3-Bromophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)meth-
anesulfonamide, Sodium Salt
##STR00079##
[0716] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (239 mg, 76%) as a white solid.
[0717] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.49-7.48 (m,
1H), 7.43-7.41 (m, 1H), 7.31-7.29 (m, 2H), 7.25-7.21 (m, 1H), 6.79
(s, 1H), 4.25 (s, 2H), 2.80-2.74 (m, 8H) and 1.99-1.92 (m, 4H).
[0718] LCMS: m/z 451 (M+H).sup.+ (ES.sup.+).
Example 20:
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(m-tolyl)methanesul-
fonamide, Sodium Salt
##STR00080##
[0720] Prepared as described for
1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl-
)methanesulfonamide, sodium salt (Example 4) to afford the title
compound (323 mg, 96%) as a white solid.
[0721] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.26 (s, 1H),
7.16-7.09 (m, 3H), 7.04-7.02 (m, 1H), 6.79 (s, 1H), 4.18 (s, 2H),
2.79-2.73 (m, 8H), 2.27 (s, 3H) and 1.97-1.90 (m, 4H).
[0722] LCMS: m/z 407 (M+Na).sup.+ (ES.sup.+).
Example 21:
3-Azido-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)
propane-1-sulfonamide, Potassium Salt
##STR00081##
[0724] To a solution of 3-azidopropane-1-sulfonamide (Intermediate
PS) (200 mg, 2.1 mmol) in THF (15 mL) was added potassium
tert-butoxide (236 mg, 2.1 mmol). The mixture was stirred at room
temperature for 45 minutes.
4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1)
(419 mg, 2.1 mmol) was added and the mixture was stirred for 2
hours at room temperature. Then the reaction mixture was
concentrated in vacuo and a part of the mixture was dissolved in
DMSO (1 mL) and submitted for purification by reversed phase column
chromatography (see "Experimental Methods", "Purification Method"
to afford an initial amount of title compound (55 mg) as a white
solid. The remainder of the batch was stored. LCMS: m/z 364
(M+H).sup.+ (ES.sup.+); 362 (M-H).sup.- (ES.sup.-).
Example 22: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)
carbamoyl)-1-phenylmethanesulfonamide
##STR00082##
[0726] To a solution of phenylmethanesulfonamide (61 mg, 355.51
.mu.mol, 1 eq) in THF (2 mL) was added t-BuONa (34 mg, 355.51
.mu.mol, 1 eq) and the mixture was stirred at 25.degree. C. for 0.5
hour. Then
4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile
(intermediate A2) (0.1 g, 355.51 .mu.mol, 1 eq) was added and the
resulting mixture was heated to 70.degree. C. and stirred for 0.1
hour. The mixture was concentrated in vacuo. The residue was
purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10
.mu.m; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN];
B %: 15%-45%, 11.5 min) to give the title compound (0.038 g, 23%
yield, 99% purity on LCMS) as a white solid.
[0727] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.59 (br s, 1H), 8.77
(d, 1H), 8.12 (S, 1H), 7.80 (dd, 1H), 7.30-7.10 (m, 7H), 4.30 (s,
2H), 3.24-3.20 (m, 1H) and 1.20 (d, 6H).
[0728] LCMS: m/z 453.3 (M+H).sup.+ (ES.sup.+).
Example 23:
N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)
carbamoyl)-1-phenylmethanesulfonamide
##STR00083##
[0730] To a solution of phenylmethanesulfonamide (60 mg, 349.28
.mu.mol, 1 eq) in THF (2 mL) was added t-BuONa (34 mg, 349.28
.mu.mol, 1 eq) and the mixture was stirred at 25.degree. C. for 0.5
hour. Then
4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine
(intermediate A3) (0.1 g, 349.28 .mu.mol, 1 eq) was added and the
resulting mixture was heated to 70.degree. C. and stirred for 0.1
hour. The mixture was concentrated in vacuo. The residue was
purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10
.mu.m; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN];
B %: 10%-40%, 11.5 min) to give the title compound (0.04 g, 25%
yield, 99% purity on LCMS) as a white solid.
[0731] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.15 (d, 1H), 7.52 (br
s, 1H), 7.34-7.11 (m, 6H), 7.10-6.95 (m, 2H), 6.87 (s, 1H), 4.27
(s, 2H), 3.85 (s, 3H), 3.25-3.19 (m, 1H) and 1.18 (d, 6H).
[0732] LCMS: m/z 458.3 (M+H).sup.+ (ES.sup.+).
Example 24:
N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)
carbamoyl)-1-phenylmethanesulfonamide
##STR00084##
[0734] To a solution of phenylmethanesulfonamide (64 mg, 375.52
.mu.mol, 1 eq) in THF (2 mL) was added t-BuONa (36 mg, 375.52
.mu.mol, 1 eq) and the mixture was stirred at 25.degree. C. for 0.5
hour. Then
4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine
(intermediate A4) (0.1 g, 375.52 .mu.mol, 1 eq) was added and the
resulting mixture was heated to 70.degree. C. and stirred for 0.1
hour. The mixture was concentrated in vacuo. The residue was
purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10
.mu.m; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN];
B %: 8%-38%, 11.5 min) to give the title compound (90.80 mg, 55%
yield, 99% purity on LCMS) as a white solid.
[0735] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.14 (d, 1H), 7.50 (br
s, 1H), 7.32-7.30 (m, 3H), 7.25-7.24 (m, 2H), 7.17 (d, 1H), 7.09
(d, 1H), 6.97 (dd, 1H), 6.80 (s, 1H), 4.37 (s, 2H), 3.87 (s, 3H),
2.94 (t, 2H), 2.85 (t, 2H) and 2.09-1.97 (m, 2H).
[0736] LCMS: m/z 438.2 (M+H).sup.+ (ES.sup.+).
Example 25:
N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)
carbamoyl)-1-phenylmethanesulfonamide
##STR00085##
[0738] A mixture of phenylmethanesulfonamide (70 mg, 408.84
.mu.mol, 1 eq) and t-BuONa (39 mg, 408.84 .mu.mol, 1 eq) in THF (2
mL) was stirred at 25.degree. C. for 10 minutes. Then
4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine
(intermediate A5) (104 mg, 408.84 .mu.mol, 1 eq) was added. The
mixture was stirred at 70.degree. C. for 10 minutes. The reaction
mixture was concentrated in vacuo. The residue was purified by
prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 .mu.m; mobile
phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %:
5%-35%, 10 min) to give the title compound (16.61 mg, 10% yield,
100% purity on LCMS) as a white solid.
[0739] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.54 (d, 2H), 7.41 (d,
2H), 7.26-7.22 (m, 4H), 7.18-7.02 (m, 2H), 6.95 (d, 1H), 4.21 (s,
2H), 2.96 (t, 2H), 2.89 (t, 2H) and 2.12-2.03 (m, 2H).
[0740] LCMS: m/z 426.2 (M+H).sup.+ (ES.sup.+).
Example 26: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)
carbamoyl)-2-methylpropane-1-sulfonamide
##STR00086##
[0742] To a solution of 2-methylpropane-1-sulfonamide (49 mg,
355.51 .mu.mol, 1 eq) (intermediate P2) in THF (2 mL) were added
t-BuONa (34 mg, 355.51 .mu.mol, 1 eq) and
4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile
(intermediate An) (100 mg, 355.51 .mu.mol, 1 eq). The reaction
mixture was stirred at 20.degree. C. for 20 minutes and then
concentrated in vacuo. The residue was purified by prep-HPLC
(column: Phenomenex Gemini C18, 150 mm*25 mm*5 .mu.m, mobile phase:
[A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 3%-33%,
12.0 min) to give the title compound (48.16 mg, 32%) as a white
solid.
[0743] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.72 (d, 1H), 8.07 (s,
1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.21 (d, 1H), 7.11 (d, 1H),
3.26-3.23 (m, 1H), 2.67-2.63 (m, 2H), 1.77-1.66 (m, 1H), 1.15 (d,
6H) and 0.84 (d, 6H).
[0744] LCMS: m/z 419.2 (M+H).sup.+ (ES.sup.+).
Example 27:
N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)
carbamoyl)-2-methylpropane-1-sulfonamide
##STR00087##
[0746] To a solution of 2-methylpropane-1-sulfonamide (intermediate
P2) (48 mg, 349.28 .mu.mol, 1 eq) in THF (2 mL) were added t-BuONa
(34 mg, 349.28 .mu.mol, 1 eq) and
4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine
(intermediate A3) (100 mg, 349.28 .mu.mol, 1 eq). The reaction
mixture was stirred at 25.degree. C. for 10 minutes and then was
concentrated in vacuo. The residue was purified by prep-HPLC
(column: Phenomenex Gemini C18, 150 mm*25 mm*5 .mu.m, mobile phase:
[A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 15%-45%,
11.5 min) to give the title compound (101.64 mg, 69% yield, 100%
purity on LCMS) as a white solid.
[0747] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.17 (d, 1H), 7.91 (s,
1H), 7.27-7.24 (m, 1H), 7.06 (dd, 1H), 6.99 (d, 1H), 6.82 (s, 1H),
3.87 (s, 3H), 3.16-3.09 (m, 1H), 3.00 (d, 2H), 1.91-1.81 (m, 1H),
1.16 (d, 6H) and 0.91 (d, 6H).
[0748] LCMS: m/z 424.2 (M+H).sup.+ (ES.sup.+).
Example 28:
N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)
carbamoyl)-2-methylpropane-1-sulfonamide
##STR00088##
[0750] To a solution of 2-methylpropane-1-sulfonamide (intermediate
P2) (55 mg, 401.36 .mu.mol, 1 eq) in THF (2 mL) were added t-BuONa
(39 mg, 401.36 .mu.mol, 1 eq) and
4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine
(intermediate A4) (167 mg, 401.36 .mu.mol, 1 eq). The reaction
mixture was stirred at 25.degree. C. for 20 minutes and then
concentrated in vacuo. The residue was purified by prep-HPLC
(column: Phenomenex Gemini C18, 150 mm*25 mm*10 .mu.m, mobile
phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN], B %: 18%-48%,
10 min) to give the title compound (16.29 mg, 10%) as a white
solid.
[0751] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.15 (d, 1H), 7.93 (br
s, 1H), 7.22 (d, 1H), 7.12 (d, 1H), 6.94-6.91 (m, 1H), 6.74 (s,
1H), 3.86 (s, 3H), 3.10 (d, 2H), 2.93 (t, 2H), 2.79 (t, 2H),
2.05-1.95 (m, 3H) and 0.95 (d, 6H).
[0752] LCMS: m/z 404.2 (M+H).sup.+ (ES.sup.+).
Example 29:
N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)
carbamoyl)-2-methylpropane-1-sulfonamide
##STR00089##
[0754] To a solution of 2-methylpropane-1-sulfonamide (intermediate
P2) (54 mg, 393.30 .mu.mol, 1 eq) in THF (2 mL) was added t-BuONa
(38 mg, 393.30 .mu.mol, 1 eq). Then the mixture was stirred at
25.degree. C. for 10 minutes. A solution of
4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine
(intermediate A5) (100 mg, 393.30 .mu.mol, 1 eq) in THF (2.5 mL)
was added. The resulting mixture was stirred at 25.degree. C. for
30 minutes and then concentrated in vacuo. The residue was purified
by prep-HPLC (Column: Xtimate C18, 250 mm*50 mm*10 .mu.m, mobile
phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %:
1%-31%, 10.0 min) to give the title compound (45.33 mg, 29% yield,
100% purity on LCMS) as a white solid.
[0755] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.54 (d, 2H), 7.40 (d,
2H), 6.96 (d, 1H), 2.95 (t, 2H), 2.89-2.83 (m, 4H), 2.09-2.03 (m,
2H), 1.96-1.91 (m, 1H) and 0.93 (d, 6H).
[0756] LCMS: m/z 392.2 (M+H).sup.+ (ES.sup.+).
Example 30: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)
carbamoyl)-2-phenylethanesulfonamide
##STR00090##
[0758] To a solution of 2-phenylethanesulfonamide (intermediate P3)
(66 mg, 355.51 .mu.mol, 1 eq) in THF (2 mL) was added t-BuONa (34
mg, 355.51 .mu.mol, 1 eq) and the mixture was stirred at 25.degree.
C. for 0.5 hour. Then
4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile
(intermediate A2) (0.1 g, 355.51 .mu.mol, 1 eq) was added and the
resulting mixture was heated to 70.degree. C. and stirred for 0.1
hour. The mixture was concentrated in vacuo. The residue was
purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10
.mu.m; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN];
B %: 12%-42%, 11.5 min) to give the title compound (0.07 g, 42%
yield, 99% purity on LCMS) as a white solid.
[0759] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.77 (br s, 1H), 8.67
(d, 1H), 8.11 (s, 1H), 7.92 (br s, 1H), 7.80 (d, 1H), 7.31-7.18 (m,
5H), 7.09 (d, 2H), 3.25-3.19 (m, 3H), 2.70-2.51 (m, 2H) and 1.17
(d, 6H).
[0760] LCMS: m/z 467.3 (M+H).sup.+ (ES.sup.+).
Example 31:
N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)
carbamoyl)-2-phenylethanesulfonamide
##STR00091##
[0762] To a solution of 2-phenylethanesulfonamide (intermediate P3)
(65 mg, 349.28 .mu.mol, 1 eq) in THF (2 mL) was added t-BuONa (34
mg, 349.28 .mu.mol, 1 eq) and the mixture was stirred at 25.degree.
C. for 0.5 hour. Then
4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine
(intermediate A3) (0.1 g, 349.28 .mu.mol, 1 eq) was added and the
resulting mixture was heated to 70.degree. C. and stirred for 0.1
hour. The mixture was concentrated in vacuo. The residue was
purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25
mm*10 .mu.m; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B:
MeCN]; B %: 22%-52%, 11 min) to give the title compound (0.0317 g,
19% yield, 99% purity on LCMS) as a white solid.
[0763] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.10 (d, 1H), 8.00 (br
s, 1H), 7.34-7.22 (m, 4H), 7.16-6.99 (m, 4H), 6.84 (s, 1H), 3.73
(s, 3H), 3.44-3.40 (m, 2H), 3.18-3.13 (m, 1H), 2.80-2.76 (m, 2H)
and 1.16 (d, 6H).
[0764] LCMS: m/z 472.2 (M+H).sup.+ (ES.sup.+).
Example 32:
N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)
carbamoyl)-2-phenylethanesulfonamide
##STR00092##
[0766] To a solution of 2-phenylethanesulfonamide (intermediate P3)
(70 mg, 375.52 .mu.mol, 1 eq) in THF (2 mL) was added t-BuONa (36
mg, 375.52 .mu.mol, 1 eq) and the mixture was stirred at 25.degree.
C. for 0.5 hour. Then
4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine
(intermediate A4) (0.1 g, 375.52 .mu.mol, 1 eq) was added and the
resulting mixture was heated to 70.degree. C. and stirred for 0.1
hour. The mixture was concentrated in vacuo. The residue was
purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25
mm*10 .mu.m; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B:
MeCN]; B %: 17%-47%, 11 min) to give the title compound (0.021 g,
12% yield, 100% purity on LCMS) as a white solid.
[0767] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.07 (d, 1H), 7.50 (br
s, 1H), 7.33-7.26 (m, 2H), 7.19-7.13 (m, 4H), 7.10-7.08 (m, 1H),
6.99 (d, 1H), 6.81 (s, 1H), 3.77 (s, 3H), 3.30-3.23 (m, 2H), 2.92
(t, 2H), 2.86-2.80 (m, 4H) and 2.07-1.98 (m, 2H).
[0768] LCMS: m/z 452.2 (M+H).sup.+ (ES.sup.+).
Example 33:
N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)
carbamoyl)-2-phenylethanesulfonamide
##STR00093##
[0770] A mixture of 2-phenylethanesulfonamide (intermediate P3) (75
mg, 404.87 .mu.mol, 1 eq) and t-BuONa (39 mg, 404.87 .mu.mol, 1 eq)
in THF (2 mL) was stirred at 25.degree. C. for 10 minutes. Then
4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine
(intermediate A5) (103 mg, 404.87 .mu.mol, 1 eq) was added. The
resulting mixture was stirred at 25.degree. C. for 10 minutes, then
warmed to 70.degree. C. and stirred for 10 minutes. The reaction
mixture was concentrated in vacuo. The residue was purified by
prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 .mu.m; mobile
phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %:
5%-35%, 10 min) to give the title compound (15.1 mg, 8% yield, 100%
purity on LCMS) as a white solid.
[0771] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.53 (d, 2H), 7.63 (br
s, 1H), 7.42 (d, 2H), 7.31 (t, 2H), 7.23-7.16 (m, 3H), 7.00 (d,
1H), 3.39-3.35 (m, 2H), 2.99 (t, 2H), 2.90-2.82 (m, 4H) and
2.10-2.06 (m, 2H).
[0772] LCMS: m/z 440.2 (M+H).sup.+ (ES.sup.+).
Example 34: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)
carbamoyl)-1-phenylethanesulfonamide
##STR00094##
[0774] To a solution of 1-phenylethanesulfonamide (intermediate P4)
(50 mg, 269.92 .mu.mol, 1 eq) in THF (2 mL) was added t-BuONa (26
mg, 269.92 .mu.mol, 1 eq). After stirring at 20.degree. C. for 10
minutes, 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile
(intermediate A2) (76 mg, 269.92 .mu.mol, 1 eq) was added. The
reaction mixture was stirred at 20.degree. C. for 20 minutes and
then concentrated in vacuo. The residue was purified by prep-HPLC
(column: Phenomenex Gemini c18, 150 mm*25 mm*10 .mu.m; mobile
phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 22%-52%,
12 min) to give the title compound (14.74 mg, 11% yield, 98% purity
on LCMS) as a white solid.
[0775] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.53 (br s, 1H), 8.77
(d, 1H), 8.10 (s, 1H), 7.97-7.93 (m, 1H), 7.77 (d, 1H), 7.32-7.24
(m, 4H), 7.23-7.19 (m, 3H), 4.57-4.54 (m, 1H), 3.15-3.12 (m, 1H),
1.46-1.40 (m, 3H) and 1.20-1.08 (m, 6H).
[0776] LCMS: m/z 467.2 (M+H).sup.+ (ES.sup.+).
Example 35:
N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)
carbamoyl)-1-phenylethanesulfonamide
##STR00095##
[0778] To a solution of 1-phenylethanesulfonamide (intermediate P4)
(50 mg, 269.92 .mu.mol, 1 eq) in THF (2 mL) was added t-BuONa (26
mg, 269.92 .mu.mol, 1 eq). The mixture was stirred at 20.degree. C.
for 10 minutes. Then
4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine
(intermediate A3) (77 mg, 269.92 .mu.mol, 1 eq) was added. The
reaction mixture was stirred at 20.degree. C. for 20 minutes and
then concentrated in vacuo. The residue was purified by prep-HPLC
(column: Xtimate C18, 150 mm*25 mm*5 .mu.m; mobile phase: [A: water
(0.05% ammonium hydroxide v/v); B: MeCN]; B %: 10%-40%, 12 min) to
give the title compound (12.98 mg, 10% yield, 100% purity on LCMS)
as a white solid.
[0779] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.40 (br s, 1H), 8.15
(d, 1H), 7.70 (br s, 1H), 7.32-7.20 (m, 6H), 7.05-7.00 (m, 2H),
6.85 (s, 1H), 4.60-4.56 (m, 1H), 3.86 (s, 3H), 3.16-3.11 (m, 1H),
1.45 (d, 3H) and 1.18 (dd, 6H).
[0780] LCMS: m/z 472.2 (M+H).sup.+ (ES.sup.+).
Example 36:
N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)
carbamoyl)-1-phenylethanesulfonamide
##STR00096##
[0782] To a solution of 1-phenylethanesulfonamide (intermediate P4)
(50 mg, 269.92 .mu.mol, 1 eq) in THF (2 mL) was added t-BuONa (26
mg, 269.92 .mu.mol, 1 eq). The mixture was stirred at 20.degree. C.
for 10 minutes. Then
4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine
(intermediate A4) (72 mg, 269.92 .mu.mol, 1 eq) was added and then
the resulting mixture was stirred at 20.degree. C. for 20 minutes.
The reaction mixture was concentrated in vacuo. The residue was
purified by prep-HPLC (column: Xtimate C18, 150 mm*25 mm*5 .mu.m;
mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B
%: 5%-35%, 12 min) to give the title compound (34.56 mg, 28% yield,
99.8% purity on LCMS) as a white solid.
[0783] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.12 (d, 1H), 7.60 (br
s, 1H), 7.33-7.30 (m, 5H), 7.19 (d, 1H), 7.09 (d, 1H), 6.94-6.92
(m, 1H), 6.77 (s, 1H), 4.69-4.66 (m, 1H), 3.86 (s, 3H), 2.93 (t,
2H), 2.81 (t, 2H), 2.07-2.01 (m, 2H) and 1.54 (d, 3H).
[0784] LCMS: m/z 452.2 (M+H).sup.+ (ES.sup.+).
Example 37:
N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)
carbamoyl)-1-phenylethanesulfonamide
##STR00097##
[0786] To a solution of 1-phenylethanesulfonamide (intermediate P4)
(75 mg, 404.87 .mu.mol, 1 eq) in THF (2 mL) was added t-BuONa (39
mg, 404.87 .mu.mol, 1 eq). Then the reaction mixture was stirred at
20.degree. C. for 10 minutes. A solution of
4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine
(intermediate A5) (103 mg, 404.87 .mu.mol, 1 eq) in THF (2 mL) was
added. The resulting mixture was stirred at 20.degree. C. for 20
minutes and then concentrated in vacuo. The residue was purified by
prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 .mu.m;
mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %:
13%-43%, 10 min) to give the title compound (63.22 mg, 35% yield,
99% purity on LCMS) as a light red solid.
[0787] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.57 (d, 2H), 7.69 (br
s, 1H), 7.37-7.30 (m, 7H), 7.02 (d, 1H), 4.75-4.67 (m, 1H), 2.98
(t, 2H), 2.84 (t, 2H), 2.14-2.08 (m, 2H) and 1.55 (d, 3H).
[0788] LCMS: m/z 440.2 (M+H).sup.+ (ES.sup.+).
Example 38:
N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)
carbamoyl)methanesulfonamide
##STR00098##
[0790] 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (326
mg, 1.36 mmol) (Intermediate A4, step F) was dissolved in THF (5
mL). Triethylamine (208 .mu.l, 1.49 mmol) was added, followed by a
solution of bis(trichloromethyl) carbonate (382 mg, 1.29 mmol) in
THF (2 mL). The thick reaction mixture was stirred at room
temperature for 1 hour. The solvent was removed in vacuo and the
solid formed was dried under high vacuum for 1 hour. The solid,
4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine, was
suspended in THF (8 mL) of which 2 mL were used later.
Methanesulfonamide (30 mg, 0.315 mmol) was suspended in THF (2 mL),
sodium tert-butoxide (2 M in THF) (175 .mu.l, 0.351 mmol) was
added, and the mixture was stirred for 30 minutes at room
temperature. Then a solution of
4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (78
mg, 0.292 mmol) in THF (2 mL), prepared earlier, was added and the
mixture was stirred overnight at room temperature. The THF was
removed in vacuo and the residue was dissolved in DMSO (2 mL) and
then purified by basic prep HPLC to afford the title compound (23.5
mg, 21%) as a colourless solid.
[0791] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.17 (d, J=5.3 Hz, 1H),
7.86 (s, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.95
(dd, J=5.3, 1.3 Hz, 1H), 6.77 (s, 1H), 3.88 (s, 3H), 3.01 (s, 3H),
2.94 (t, J=7.4 Hz, 2H), 2.82 (t, J=7.4 Hz, 2H), 2.04 (p, J=7.5 Hz,
2H). NH not observed.
[0792] LCMS; m/z 362.2 (M+H).sup.+ (ES.sup.+); 360.0 (M-H).sup.-
(ES.sup.-).
Example 39:
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-phenylethanesulfona-
mide
##STR00099##
[0794] NaO.sup.tBu (2 M in THF, 0.16 mL, 0.32 mmol) was added to a
solution of 1-phenylethanesulfonamide (Intermediate P4) (60 mg,
0.308 mmol) in THF (3.5 mL) at room temperature. The mixture was
stirred for 1 hour, before
4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1)
(0.067 g, 0.338 mmol) was added in a single portion and the
reaction mixture was stirred for 21 hours at room temperature.
EtOAc (10 mL) was added, followed by aq 2 M NaOH (.about.0.2 mL)
and water (3 mL). The phases were separated and the organic phase
was extracted with water (3 mL). The combined aqueous phases were
filtered and purified by chromatography on RP Flash C18 (12 g
column, 0-100% MeCN/10 mM ammonium bicarbonate) to afford the title
compound (15 mg, 13%) as a white solid.
[0795] LCMS; m/z 385.3 (M+H).sup.+ (ES.sup.+).
[0796] .sup.1H NMR (DMSO-d6) .delta. 10.10 (s, 1H), 7.87 (s, 1H),
7.40 (m, 5H), 6.97 (s, 1H), 4.88 (q, J=7.1 Hz, 1H), 2.82 (t, J=7.4
Hz, 4H), 2.69 (t, J=7.4 Hz, 4H), 2.00 (p, J=7.4 Hz, 4H), 1.69 (d,
J=7.2 Hz, 3H).
Example 40:
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-phenylethanesulfona-
mide
##STR00100##
[0798] Prepared according to the general procedure of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-phenylethanesulfona-
mide (Example 39) from 2-phenylethanesulfonamide (Intermediate P3)
and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1)
to afford the title compound (35 mg, 37%) as a colourless
solid.
[0799] .sup.1H NMR (DMSO-d6) .delta. 10.35 (s, 1H), 8.18 (s, 1H),
7.37-7.29 (m, 2H), 7.29-7.21 (m, 3H), 6.97 (s, 1H), 3.77-3.65 (m,
2H), 3.09-2.97 (m, 2H), 2.82 (t, J=7.4 Hz, 4H), 2.70 (t, J=7.4 Hz,
4H), 2.03-1.93 (m, 4H).
[0800] LCMS; m/z 385.4 (M+H).sup.+ (ES.sup.+).
Examples--Biological Studies
[0801] NLRP3 and Pyroptosis
[0802] It is well established that the activation of NLRP3 leads to
cell pyroptosis and this feature plays an important part in the
manifestation of clinical disease (Yan-gang Liu et al., Cell Death
& Disease, 2017, 8(2), e2579; Alexander Wree et al.,
Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of
Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al.,
Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie &
Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65;
Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24),
10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4,
e644). Therefore, it is anticipated that inhibitors of NLRP3 will
block pyroptosis, as well as the release of pro-inflammatory
cytokines (e.g. IL-1.beta.) from the cell.
[0803] THP-1 Cells: Culture and Preparation
[0804] THP-1 cells (ATCC # TIB-202) were grown in RPMI containing
L-glutamine (Gibco #11835) supplemented with ImM sodium pyruvate
(Sigma # S8636) and penicillin (100 units/ml)/streptomycin (0.1
mg/ml) (Sigma # P4333) in 10% Fetal Bovine Serum (FBS) (Sigma #
F0804). The cells were routinely passaged and grown to confluency
(.about.10.sup..delta. cells/ml). On the day of the experiment,
THP-1 cells were harvested and resuspended into RPMI medium
(without FBS). The cells were then counted and viability (>90%)
checked by Trypan blue (Sigma # T8154). Appropriate dilutions were
made to give a concentration of 625,000 cells/ml. To this diluted
cell solution was added LPS (Sigma # L4524) to give a 1 .mu.g/ml
Final Assay Concentration (FAC). 40l of the final preparation was
aliquoted into each well of a 96-well plate. The plate thus
prepared was used for compound screening.
[0805] THP-1 Cells Pyroptosis Assay
[0806] The following method step-by-step assay was followed for
compound screening. [0807] 1. Seed THP-1 cells (25,000 cells/well)
containing 1.0 .mu.g/ml LPS in 40 .mu.l of RPMI medium (without
FBS) in 96-well, black walled, clear bottom cell culture plates
coated with poly-D-lysine (VWR #734-0317) [0808] 2. Add 5 .mu.l
compound (8 points half-log dilution, with 10 .mu.M top dose) or
vehicle (DMSO 0.1% FAC) to the appropriate wells [0809] 3. Incubate
for 3 hrs at 37.degree. C. in 5% CO.sub.2 [0810] 4. Add 5 .mu.l
nigericin (Sigma # N7143) (FAC 5 .mu.M) to all wells [0811] 5.
Incubate for 1 hr at 37.degree. C. and 5% CO.sub.2 [0812] 6. At the
end of the incubation period, spin plates at 300.times.g for 3 mins
and remove supernatant [0813] 7. Then add 50 .mu.l of resazurin
(Sigma # R7017) (FAC 100 .mu.M resazurin in RPMI medium without
FBS) and incubate plates for a further 1-2 hrs at 37.degree. C. and
5% CO.sub.2 [0814] 8. Plates were read in an Envision reader at Ex
560 nm and Em 590 nm [0815] 9. IC.sub.50 data is fitted to a
non-linear regression equation (log inhibitor vs response-variable
slope 4-parameters)
[0816] 96-Well Plate Map
TABLE-US-00005 1 2 3 4 5 6 7 8 9 10 11 12 A High Comp 1 Comp 2 Comp
3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low B High Comp
1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10
Low C High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8
Comp 9 Comp 10 Low D High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6
Comp 7 Comp 8 Comp 9 Comp 10 Low E High Comp 1 Comp 2 Comp 3 Comp 4
Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low F High Comp 1 Comp 2
Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low G High
Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp
10 Low H High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp
8 Comp 9 Comp 10 Low High MCC950 (10 uM) Compound 8-point half-log
dilution Low Drug free control
[0817] The results of the pyroptosis assay performed are summarised
in Table 1 below as THP IC.sub.50.
[0818] Human Whole Blood IL113 Release Assay
[0819] For systemic delivery, the ability to inhibit NLRP3 when the
compounds are present within the bloodstream is of great
importance. For this reason, the NLRP3 inhibitory activity of a
number of compounds in human whole blood was investigated in
accordance with the following protocol.
[0820] Human whole blood in Li-heparin tubes was obtained from
healthy donors from a volunteer donor panel. [0821] 1. Plate out 80
.mu.l of whole blood containing 1 .mu.g/ml of LPS in 96-well, clear
bottom cell culture plate (Corning #3585) [0822] 2. Add 10 .mu.l
compound (8 points half-log dilution with 10 .mu.M top dose) or
vehicle (DMSO 0.1% FAC) to the appropriate wells [0823] 3. Incubate
for 3 hrs at 37.degree. C., 5% CO.sub.2 [0824] 4. Add 10 .mu.l
nigericin (Sigma # N7143) (10 .mu.M FAC) to all wells [0825] 5.
Incubate for 1 hr at 37.degree. C., 5% CO.sub.2 [0826] 6. At the
end of the incubation period, spin plates at 300.times.g for 5 mins
to pellet cells and remove 20 .mu.l of supernatant and add to
96-well v-bottom plates for IL-1.beta. analysis (note: these plates
containing the supernatants can be stored at -80.degree. C. to be
analysed at a later date) [0827] 7. IL-1.beta. was measured
according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1
Kit AL220F-5000) [0828] 8. IC.sub.50 data is fitted to a non-linear
regression equation (log inhibitor vs response-variable slope
4-parameters)
[0829] The results of the human whole blood assay are summarised in
Table 1 below as HWB IC.sub.50.
TABLE-US-00006 TABLE 1 NLRP3 inhibitory activity in THP-1 Cells
(.ltoreq.10 .mu.M = `+`, .ltoreq.2.0 .mu.M = `++`, .ltoreq.1.5
.mu.M = `+++`, .ltoreq.1.0 .mu.M = `++++`, not determined = `ND`).
NLRP3 inhibitory activity in HWB (>10 .mu.M = `.circle-solid.`,
.ltoreq.10 .mu.M = `.circle-solid..circle-solid.`, .ltoreq.7.5
.mu.M = `.circle-solid..circle-solid..circle-solid.`, .ltoreq.5.0
.mu.M = `.circle-solid..circle-solid..circle-solid..circle-solid.`,
ND = not determined). Example No THP IC.sub.50 HWB IC.sub.50 1 ++++
.circle-solid..circle-solid..circle-solid..circle-solid. 2 ++++ ND
3 ++++ .circle-solid..circle-solid..circle-solid..circle-solid. 4
++++ .circle-solid. 5 ++++
.circle-solid..circle-solid..circle-solid. 6 ++++ .circle-solid. 7
++++ .circle-solid..circle-solid..circle-solid..circle-solid. 8
++++ .circle-solid..circle-solid..circle-solid..circle-solid. 9
++++ .circle-solid..circle-solid..circle-solid..circle-solid. 10
++++ .circle-solid..circle-solid..circle-solid. 11 ++++
.circle-solid..circle-solid. 12 ++++ .circle-solid. 13 ++++
.circle-solid. 14 ++++ .circle-solid..circle-solid..circle-solid.
15 ++++ .circle-solid. 16 ++++ ND 17 ++++ ND 18 ++++ ND 19 ++++
.circle-solid. 20 ++++ .circle-solid..circle-solid..circle-solid.
21 ++++ .circle-solid..circle-solid..circle-solid..circle-solid. 22
+ ND 23 ++++ ND 24 ++ ND 25 + ND 26 + ND 27 ++++ ND 28 ++++ ND 29
++++ ND 30 ++++ ND 31 ++++ ND 32 ++++ ND 33 ++++
.circle-solid..circle-solid..circle-solid. 34 + ND 35 ++ ND 36 ++++
ND 37 ++ ND 38 ++++ ND 39 ++++ .circle-solid..circle-solid. 40 ++++
.circle-solid.
[0830] As is evident from the results presented in Table 1,
surprisingly in spite of the structural differences versus the
prior art compounds, the compounds of the invention show high
levels of NLRP3 inhibitory activity. In particular, it is evident
from the data that the compounds of the invention are particularly
suited to topical routes of administration.
[0831] It will be understood that the present invention has been
described above by way of example only. The examples are not
intended to limit the scope of the invention. Various modifications
and embodiments can be made without departing from the scope and
spirit of the invention, which is defined by the following claims
only.
* * * * *